Serotonin receptor modulators

ABSTRACT

Certain biphenyic compounds are serotonin modulators useful in the treatment of serotonin-mediated diseases.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No. 14/051,199, filed on Oct. 10, 2013, which is a divisional of U.S. patent application Ser. No. 13/126,223, filed on Apr. 27, 2011, now U.S. Pat. No. 8,642,583, which is a national phase of International Application No. PCT/US2009/062627, filed on Oct. 29, 2009, which claims the benefit of U.S. Provisional Patent Application No. 61/109,903, filed on Oct. 30, 2008, each of which are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

There is provided by the present invention compounds that are serotonin receptor modulators. More particularly, there is provided by the present invention certain compounds that are serotonin receptor modulators useful for the treatment of disease states mediated by serotonin receptor activity.

BACKGROUND OF THE INVENTION

Serotonin (5-hydroxytryptamine, 5-HT) is a major neurotransmitter eliciting effects via a multiplicity of receptors. To date, at least fifteen different 5-HT receptors have been identified, largely as the result of cDNA cloning. These receptors have been grouped into seven families (5-HT₁ through 5-HT₇) (Hoyer, D. et al. Pharmacol. Biochem. Behav., 2002, 71, 533-554).

Fourteen of the fifteen cloned 5-HT receptors are expressed in the brain. 5-HT is implicated in many disease states, particularly conditions of the central nervous system including; depression, anxiety, schizophrenia, eating disorders, obsessive compulsive disorder, learning and memory dysfunction, migraine, chronic pain, sensory perception, motor activity, temperature regulation, nociception, sexual behavior, hormone secretion, and cognition.

The identification of multiple 5-HT receptors has provided the opportunity to characterize existing therapeutic agents thought to act via the serotonergic system. Consequently, this has led to the realization that many drugs have non-selective properties (Roth, B. L. et al., Neuroscientist, 2000, 6(4), 252-262). For example, the antipsychotic drugs, clozapine, chlorpromazine, haloperidol and olanzapine exhibit affinities for multiple serotonin receptors in addition to other families of receptors. Similar behavior has been noted for antidepressants including imipramine, nortriptaline, fluoxetine and sertraline. Similarly, the anti-migraine agent sumatriptan exhibits high affinity for several serotonin receptors. While the lack of selectivity often contributes to a favorable therapeutic outcome, it can also cause undesirable and dose-limiting side effects (Stahl, S. M., Essential Psychopharmacology, 2^(nd) ed., Cambridge University Press, Cambridge, U.K., 2000). For example, the inhibition of serotonin and norepinephrine uptake together with 5-HT₂ receptor blockade is responsible for the therapeutic effects of the tricyclic antidepressants. In contrast, their blockade of histamine H₁, muscarinic and alpha-adrenergic receptors can lead to sedation, blurred vision and orthostatic hypertension respectively. Likewise, the atypical antipsychotics, including olanzapine and clozapine, are considered to have positive therapeutic effects attributable to their actions at 5-HT₂, D₂ and 5-HT₇ receptors. Conversely, their side effect liability is due to their affinities for a range of dopaminergic, serotonergic and adrenergic receptors.

Elucidating selective ligands has the potential to ameliorate untoward pharmacologies and provide novel efficacious therapies. More importantly, the ability to obtain compounds which portray receptor selectivity provides the prospect to target distinct therapeutic mechanisms and improve clinical responses with a single drug. Consequently, there remains a need for potent serotonin receptor modulators with desirable pharmaceutical properties.

SUMMARY OF THE INVENTION

Certain compounds have now been found to have 5HT-modulating activity, in particular 5HT₇ and/or serotonin transporter modulating activity. In particular, the invention is directed to the general and preferred embodiments defined, respectively, and by the independent and dependent claims appended hereto, which are incorporated by reference herein.

Thus, in one general aspect, the invention relates to compounds of Formula (I):

wherein R¹ is —H₁, —C₁₋₄alkyl, monocyclic cycloalkyl, phenyl, or benzyl; m is 1, 2 or 3, n is 1 or 2, with the proviso that if m is 2, then n is not 1; R² and R³ are each independently —H or —C₁₋₄alkyl; R⁴ is —H, F, C₁₋₄alkyl, or R⁴ is —OH when L is —CH₂—, —CF₂—, or —CHF—, —OCH₂—, or —OCH(CH₃)—; L is —O—, —CH₂—, —OCH₂—, —OCH(CH₃)—, —CH₂O—, —CF₂—, or —CHF—; Z is —O—, —C(O)—, —OCH(R^(b))—, or —OCH₂C(R^(c))(R^(d))—;

where

-   -   where R^(b) is —H; a —C₁₋₄alkyl group unsubstituted or         substituted with OH or halo; —CO₂C₁₋₄alkyl; or —CO₂H; and     -   R^(c) and R^(d) are each independently —H, —C₁₋₄alkyl,         —O—C₁₋₄alkyl, or halo;         -   or R^(c) and R^(d) taken together form an oxime, a C₁₋₄alkyl             oxime, or a carbonyl group;         -   or R^(c) and R^(d) taken together with the carbon to which             they are attached form a C₃₋₆cycloalkyl group;             R⁵ is:

i) a phenyl or phenoxy group, unsubstituted or substituted with one, two, or three R^(g) substituents;

-   -   where each R^(g) substituent is selected from the group         consisting of: —C₁₋₆alkyl, —OH, —OC₁₋₆alkyl, —CN, —NO₂,         —C(O)C₁₋₆alkyl, —S(O)₀₋₂—C₁₋₆alkyl, —OS(O)₀₋₂—C₁₋₆alkyl,         —SO₂CF₃, —SCF₃, halo, —CF₃, —OCF₃, —CO₂H, —CO₂C₁₋₆alkyl, —CH₂OH,         monocyclic cycloalkyl, phenyl, thiophenyl, benzhydryl, and         oxadiazolyl;     -   or two R^(g) substituents taken together form —OCH₂O—, —OCF₂O—,         or —OCH₂CH₂O—;

ii) a naphthyl group, unsubstituted or substituted with C₁₋₄alkyl or halo;

iii) a monocyclic heteroaryl group, unsubstituted or substituted with one, two, or three R^(g) substituents;

iv) a fused bicyclic heteroaryl group, unsubstituted or substituted with C₁₋₄alkyl or halo;

v) a monocyclic cycloalkyl group, optionally fused to a phenyl ring, and unsubstituted or substituted with one or two substituents selected from the group consisting of: —C₁₋₄alkyl, —OC₁₋₄alkyl, halo, —CF₃, oxime, —C₁₋₄alkyl oxime, or phenyl; and

vi) a monocyclic heterocycloalkyl group, optionally fused to or substituted with phenyl;

X is C or N; and

R⁶ or R⁷ are each independently —H, halo, —CF₃, thiophene, or —C(O)N(R^(x))R^(y);

wherein R^(x) and R^(y) are each independently —H or —C₁₋₄alkyl.

The invention also relates to stereoisomeric forms, hydrates, solvates, pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of compounds of Formula (I). In certain preferred embodiments, the compound of Formula (I) is a compound selected from those species described or exemplified in the detailed description below.

In a further general aspect, the invention relates to pharmaceutical compositions each comprising: (a) an effective amount of an agent selected from compounds of Formula (I) and stereoisomeric forms, hydrates, solvates, pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites thereof; and (b) a pharmaceutically acceptable excipient.

In another general aspect, the invention is directed to a method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition (collectively, “indications”) mediated by 5HT₇ activity, comprising administering to the subject in need of such treatment an effective amount of a compound of Formula (I), or a stereoisomeric form, hydrate, solvate, pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite of such compound. In certain preferred embodiments of the inventive method, the disease, disorder, or medical condition is selected from: cognitive disorders, sleep disorders, psychiatric disorders, and other disorders.

Preferred embodiments, features, and advantages of the invention will be apparent from the following detailed description and through practice of the invention.

DETAILED DESCRIPTION OF THE INVENTION AND ITS PREFERRED EMBODIMENTS

The invention may be more fully appreciated by reference to the following detailed description, including the following glossary of terms and the concluding examples. For the sake of brevity, the disclosures of the publications, including patents, cited in this specification are herein incorporated by reference.

The terms “including”, “containing” and “comprising” are used herein in their open, non-limiting sense.

The term “alkyl” refers to a straight- or branched-chain alkyl group having from 1 to 12 carbon atoms in the chain. Examples of alkyl groups include methyl (Me, which may also be structurally depicted by a bond, “/”), ethyl (Et), n-propyl (Pr), isopropyl (iPr), butyl (nBu), isobutyl (iBu), sec-butyl (sBu), tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and so on.

The term “cycloalkyl” refers to a saturated or partially saturated, monocyclic, fused polycyclic, or spiro polycyclic carbocycle having from 3 to 12 ring atoms per carbocycle. Illustrative examples of cycloalkyl groups include the following entities (depicted without their bonds of attachment):

A “heterocycloalkyl” refers to a monocyclic, or fused, bridged, or spiro polycyclic ring structure that is saturated or partially saturated and has from 3 to 12 ring atoms per ring structure selected from carbon atoms and up to three heteroatoms selected from nitrogen, oxygen, and sulfur. The ring structure may optionally contain up to two oxo groups on carbon or sulfur ring members. Illustrative examples (depicted without their bonds of attachment) include:

The term “heteroaryl” refers to a monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms per heterocycle. Illustrative examples of heteroaryl groups include the following entities (depicted without their bonds of attachment):

Those skilled in the art will recognize that the species of cycloalkyl, heterocycloalkyl, and heteroaryl groups listed or illustrated above are not exhaustive, and that additional species within the scope of these defined terms may also be selected.

The term “halogen” represents chlorine, fluorine, bromine or iodine. The term “halo” represents chloro, fluoro, bromo or iodo.

The term “substituted” means that the specified group or moiety bears one or more substituents. The term “unsubstituted” means that the specified group bears no substituents. The term “optionally substituted” means that the specified group is unsubstituted or substituted by one or more substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system. In cases where a specified moiety or group is not expressly noted as being optionally substituted or substituted with any specified substituent, it is understood that such a moiety or group is intended to be unsubstituted.

Any formula given herein is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms. In particular, compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric forms. It is understood that some compounds referred to herein are chiral and/or have geometric isomeric centers, for example E- and Z-isomers. All optical isomers and stereoisomers of the compounds of any general structural formula, and mixtures thereof, are considered within the scope of the formula. Thus, any general formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof. Furthermore, certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomers. Additionally, any general formula given herein is intended to embrace hydrates, solvates, and polymorphs of such compounds, and mixtures thereof. Furthermore, certain compounds referred to herein can exist in solvated as well as unsolvated forms. It is understood that this invention encompasses all such solvated and unsolvated forms that possess the activity that characterizes the compounds of this invention.

In another example, a zwitterionic compound is encompassed herein by referring to a compound that is known to form a zwitterion, even if it is not explicitly named in its zwitterionic form. Terms such as zwitterion, zwitterions, and their synonyms zwitterionic compound(s) are standard IUPAC-endorsed names that are well known and part of standard sets of defined scientific names. In this regard, the name zwitterion is assigned the name identification CHEBI:27369 by the Chemical Entities of Biological Interest (ChEBI) dictionary of molecular entities. As generally well known, a zwitterion or zwitterionic compound is a neutral compound that has formal unit charges of opposite sign. Sometimes these compounds are referred to by the term “inner salts”. Other sources refer to these compounds as “dipolar ions”, although the latter term is regarded by still other sources as a misnomer. As a specific example, aminoethanoic acid (the amino acid glycine) has the formula H₂NCH₂COOH, and it exists in some media (in this case in neutral media) in the form of the zwitterion ⁺H₃NCH₂COO⁻. Zwitterions, zwitterionic compounds, inner salts and dipolar ions in the known and well established meanings of these terms are within the scope of this invention, as would in any case be so appreciated by those of ordinary skill in the art. Because there is no need to name each and every embodiment that would be recognized by those of ordinary skill in the art, no structures of the zwitterionic compounds that are associated with the compounds of this invention are given explicitly herein. They are, however, part of the embodiments of this invention. No further examples in this regard are provided herein because the interactions and transformations in a given medium that lead to the various forms of a given compound are known by any one of ordinary skill in the art.

Any general formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures of the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, and ¹²⁵I, respectively. Such isotopically labeled compounds are useful in metabolic studies (preferably with ¹⁴C), reaction kinetic studies (with, for example ²H or ³H), detection or imaging techniques (such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an ¹⁸F or ¹¹C labeled compound may be particularly preferred for PET or SPECT studies. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

When referring to a formula given herein, the selection of a particular moiety from a list of possible species for a specified variable is not intended to define the moiety for the variable appearing elsewhere. In other words, where a variable appears more than once in a formula, the choice of the species from a specified list is independent of the choice of the species for the same variable elsewhere in the formula unless otherwise indicated.

By way of a first example on substituent terminology, if substituent S¹ _(example) is one of S₁ and S₂, and substituent S² _(example) is one of S₃ and S₄, then these assignments refer to embodiments of this invention given according to the choices S¹ _(example) is S₁ and S² _(example) is S₃; S¹ _(example) is S₁ and S² _(example) is S₄; S¹ _(example) is S₂ and S² _(example) is S₃; S¹ _(example) is S₂ and S² _(example) is S₄; and equivalents of each one of such choices. The shorter terminology “S¹ _(example) is one of S₁ and S₂, and S² _(example) is one of S₃ and S₄” is accordingly used herein for the sake of brevity, but not by way of limitation. The foregoing first example on substituent terminology, which is stated in generic terms, is meant to illustrate the various substituent assignments described herein. The foregoing convention given herein for substituents extends, when applicable, to members such as R¹, R², A, X⁴, X⁵, X⁶, X⁷, R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), R^(h), R^(i), R^(j), R^(k), R^(l), R^(m), and R^(o), and any other generic substituent symbol used herein.

Furthermore, when more than one assignment is given for any member or substituent, embodiments of this invention comprise the various groupings that can be made from the listed assignments, taken independently, and equivalents thereof. By way of a second example on substituent terminology, if it is herein described that substituent S_(example) is one of S₁, S₂, and S₃, this listing refers to embodiments of this invention for which S_(example) is S₁; S_(example) is S₂; S_(example) is S₃; S_(example) is one of S₁ and S₂; S_(example) is one of S₁ and S₃; S_(example) is one of S₂ and S₃; S_(example) is one of S₁, S₂ and S₃; and S_(example) is any equivalent of each one of these choices. The shorter terminology “S_(example) is one of S₁, S₂, and S₃” is accordingly used herein for the sake of brevity, but not by way of limitation. The foregoing second example on substituent terminology, which is stated in generic terms, is meant to illustrate the various substituent assignments described herein. The foregoing convention given herein for substituents extends, when applicable, to members such as as R¹, R², A, X⁴, X⁵, X⁶, X⁷, R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), R^(h), R^(i), R^(j), R^(k), R^(l), R^(m), and R^(o), and any other generic substituent symbol used herein.

The nomenclature “C_(i-j)” with j>i, when applied herein to a class of substituents, is meant to refer to embodiments of this invention for which each and every one of the number of carbon members, from i to j including i and j, is independently realized. By way of example, the term C₁₋₃ refers independently to embodiments that have one carbon member (C₁), embodiments that have two carbon members (C₂), and embodiments that have three carbon members (C₃).

The term C_(n-m)alkyl refers to an aliphatic chain, whether straight or branched, with a total number N of carbon members in the chain that satisfies n≤N≤m, with m>n. Any disubstituent referred to herein is meant to encompass the various attachment possibilities when more than one of such possibilities are allowed. For example, reference to disubstituent -A-B—, where A≠B, refers herein to such disubstituent with A attached to a first substituted member and B attached to a second substituted member, and it also refers to such disubstituent with A attached to the second substituted member and B attached to the first substituted member.

The compounds of Formula (I) and their pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of the present invention are useful as serotonin receptor modulators in the methods of the invention.

A “pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of a compound represented by Formula (I), that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, G. S. Paulekuhn, et al., “Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database”, J. Med. Chem., 2007, 50:6665-72, S. M. Berge, et al., “Pharmaceutical Salts”, J Pharm Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Examples of pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. A compound of Formula (I) may possess a sufficiently acidic group, a sufficiently basic group, or both types of functional groups, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.

Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

When the compound of Formula (I) contains a basic nitrogen, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric acid, an amino acid, such as aspartic acid, glutaric acid or glutamic acid, an aromatic acid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, a sulfonic acid, such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, any compatible mixture of acids such as those given as examples herein, and any other acid and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology.

When the compound of Formula (I) is an acid, such as a carboxylic acid or sulfonic acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide, any compatible mixture of bases such as those given as examples herein, and any other base and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology. Illustrative examples of suitable salts include organic salts derived from amino acids, such as N-methyl-D-glucamine, lysine, choline, glycine and arginine, ammonia, carbonates, bicarbonates, primary, secondary, and tertiary amines, and cyclic amines, such as tromethamine, benzylamines, pyrrolidines, piperidine, morpholine, and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

The invention also relates to pharmaceutically acceptable prodrugs of the compounds of Formula (I), and treatment methods employing such pharmaceutically acceptable prodrugs. The term “prodrug” means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the compound of Formula (I). A “pharmaceutically acceptable prodrug” is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject. Illustrative procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

Exemplary prodrugs include compounds having an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues, covalently joined through an amide or ester bond to a free amino, hydroxy, or carboxylic acid group of a compound of Formula (I). Examples of amino acid residues include the twenty naturally occurring amino acids, commonly designated by three letter symbols, as well as 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, ornithine and methionine sulfone.

Additional types of prodrugs may be produced, for instance, by derivatizing free carboxyl groups of structures of Formula (I) as amides or alkyl esters. Representative pharmaceutically acceptable amides of the invention include those derived from ammonia, primary C₁₋₆ alkyl amines and secondary di(C₁₋₆alkyl) amines. Secondary amines include 5- or 6-membered heterocyclic or heteroaromatic ring moieties containing at least one nitrogen atom and optionally between 1 and 2 additional heteroatoms. Preferred amides are derived from ammonia, C₁₋₃alkyl primary amines, and di(C₁₋₂alkyl)amines. Representative pharmaceutically acceptable esters of the invention include C₁₋₇alkyl, C₅₋₇cycloalkyl, phenyl, and phenyl(C₁₋₆)alkyl esters. Preferred esters include methyl esters. Prodrugs may also be prepared by derivatizing free hydroxy groups using groups including hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, following procedures such as those outlined in Fleisher et al., Adv. Drug Delivery Rev. 1996, 19, 115-130. Carbamate derivatives of hydroxy and amino groups may also yield prodrugs. Carbonate derivatives, sulfonate esters, and sulfate esters of hydroxy groups may also provide prodrugs. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group may be an alkyl ester, optionally substituted with one or more ether, amine, or carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, is also useful to yield prodrugs. Prodrugs of this type may be prepared as described in Robinson et al., J Med Chem. 1996, 39 (1), 10-18. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including ether, amine, and carboxylic acid functionalities.

The present invention also relates to pharmaceutically active metabolites of the compounds of Formula (I), which may also be used in the methods of the invention. A “pharmaceutically active metabolite” means a pharmacologically active product of metabolism in the body of a compound of Formula (I) or salt thereof. Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini, et al., J Med Chem. 1997, 40, 2011-2016; Shan, et al., J Pharm Sci. 1997, 86 (7), 765-767; Bagshawe, Drug Dev Res. 1995, 34, 220-230; Bodor, Adv Drug Res. 1984, 13, 224-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen, et al., eds., Harwood Academic Publishers, 1991).

The compounds of Formula (I) and their pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of the present invention are useful as modulators of the seratonin receptor in the methods of the invention. As such modulators, the compounds may act as antagonists, agonists, or inverse agonists. The term “modulators” include both inhibitors and activators, where “inhibitors” refer to compounds that decrease, prevent, inactivate, desensitize or down-regulate seratonin receptor expression or activity, and “activators” are compounds that increase, activate, facilitate, sensitize, or up-regulate seratonin receptor expression or activity.

Many of the compounds of the present invention are 5-HT₇ modulators that act as 5-HT₇ antagonists. As such, the compounds are useful in the treatment of 5-HT₇-mediated disease in which a decrease, prevention, inactivation, desensitization or down-regulation of serotonin receptor expression or activity is required.

The term “treat” or “treating” as used herein is intended to refer to administration of an active agent or composition of the invention to a subject for the purpose of effecting a therapeutic or prophylactic benefit through modulation of serotonin receptor activity. Treating includes reversing, ameliorating, alleviating, inhibiting the progress of, lessening the severity of, or preventing a disease, disorder, or condition, or one or more symptoms of such disease, disorder or condition mediated through modulation of serotonin receptor activity. The term “subject” refers to a mammalian patient in need of such treatment, such as a human.

In treatment methods according to the invention, an effective amount of a pharmaceutical agent according to the invention is administered to a subject suffering from or diagnosed as having such a disease, disorder, or condition. An “effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic or prophylactic benefit in patients in need of such treatment for the designated disease, disorder, or condition. Effective amounts or doses of the compounds of the present invention may be ascertained by routine methods such as modeling, dose escalation studies or clinical trials, and by taking into consideration routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the compound, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician.

The invention may be particularly useful in the treatment or prevention of diseases, disorders, or conditions mediated by serotonin receptor activity, such as: central nervous system disorders such as sleep disorders (including insomnia), depression/anxiety, generalized anxiety disorder, schizophrenia, bipolar disorders, cognitive disorders, mild cognitive impairment, Alzheimer's disease, Parkinson's disease, psychotic disorders, phobic disorders, obsessive-compulsive disorder, mood disorders, post-traumatic stress and other stress-related disorders, migraine, pain, eating disorders, obesity, sexual dysfunction, metabolic disturbances, hormonal imbalance, hot flashes associated with menopause, alcohol abuse, drug abuse, and addictive disorders including drug addiction and alcohol addiction. Further diseases associated with serotonin receptor activity for which the compounds may be useful for treating are nausea, inflammation, centrally mediated hypertension, sleep/wake disturbances, jetlag, and circadian rhythm abnormalities. The compounds may also be used in the treatment and prevention of hypotension, peripheral vascular disorders, cardiovascular shock, renal disorders, gastric motility, diarrhea, spastic colon, irritable bowel disorders, ischemias, septic shock, urinary incontinence and other disorders related to the gastrointestinal and vascular systems. In addition, compounds of the present invention may be used in methods for treating or preventing a range of ocular disorders including glaucoma, optic neuritis, diabetic retinopathy, retinal edema, and age-related macular degeneration. Symptoms or disease states are intended to be included within the scope of “medical conditions, disorders, or diseases.”

The compounds of the present invention are 5-HT₇ modulators, many of which are 5-HT₇ antagonists. As such, the compounds are useful in the treatment of 5-HT₇ mediated disease states. Where the compounds possess substantial 5-HT₇ modulating activity, they may be particularly useful in methods for treating depression/anxiety, sleep/wake disturbances, sleep disorders, jet lag, migraine, urinary incontinence, gastric motility, and irritable bowel disorders, hypertension, analgesic, and irritable bowel syndrome.

Particularly, as serotonin receptor modulators, the compounds of the present invention are useful in the treatment or prevention of depression, anxiety, sleep disorders, and circadian rhythm abnormalities.

The compounds of the invention are used, alone or in combination with one or more other active ingredients, to formulate pharmaceutical compositions of the invention. In addition, the compounds of the invention may be used in combination with additional active ingredients in the treatment of the above conditions. In an exemplary embodiment, additional active ingredients are those that are known or discovered to be effective in the treatment of conditions, disorders, or diseases mediated by serotonin receptors or that are active against another target associated with the particular condition, disorder, or disease. Suitable examples include: H₁ receptor antagonists, H₂ receptor antagonists, H₃ receptor antagonists, topiramate (TOPAMAX™), and neurotransmitter modulators such as norepinephrine reuptake inhibitors (NRIs), selective serotonin reuptake inhibitors (SSRIs), noradrenergic reuptake inhibitors, non-selective serotonin re-uptake inhibitors (NSSRIs), acetylcholinesterase inhibitors (such as tetrahydroaminoacridine, Donepezil (ARICEPT™), Rivastigmine, or Galantamine (REMINYL™)), modafinil, anti-psychotics, sedatives, monoamine oxidase inhibitors (MAOs), and tricyclic antidepressants (TCAs). The combination may serve to increase efficacy (e.g., by including in the combination a compound potentiating the potency or effectiveness of a compound according to the invention), decrease one or more side effects, or decrease the required dose of the compound according to the invention. In preferred embodiments, the combination method employs doses containing additional active ingredients in the range of about 20 to 300 mg per dose.

A pharmaceutical composition of the invention comprises: (a) an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite thereof; and (b) a pharmaceutically acceptable excipient.

A “pharmaceutically acceptable excipient” refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of a agent and that is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

Delivery forms of the pharmaceutical compositions containing one or more dosage units of the active agents may be prepared using suitable pharmaceutical excipients and compounding techniques known or that become available to those skilled in the art. It is anticipated that the compounds of the invention can be administered by oral or parenteral routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical administration, and inhalation. For oral administration, the compounds of the invention will generally be provided in the form of tablets or capsules or as an aqueous solution or suspension. Tablets for oral use may include the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservatives. Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate and lactose. Cornstarch and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.

Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, compounds of the invention may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the compound of the invention with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.

Liquids for oral administration may be in the form of suspensions, solutions, emulsions or syrups or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.

The active agents of this invention may also be administered by non-oral routes. For intramuscular, intraperitoneal, subcutaneous and intravenous use, the compounds of the invention will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Aqueous suspensions according to the invention may include suspending agents such as cellulose derivatives, sodium alginate, polyvinyl-pyrrolidone and gum tragacanth, and a wetting agent such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.

For topical administration, the compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle. Another mode of administering the compounds of the invention may utilize a patch formulation to affect transdermal delivery.

Compounds of the invention may alternatively be administered in methods of this invention by inhalation, via the nasal or oral routes, e.g., in a spray formulation also containing a suitable carrier.

Effective doses of the compounds of the present invention may be ascertained by conventional methods. The specific dosage level required for any particular patient will depend on a number of factors, including severity of the condition being treated, the route of administration and the weight of the patient. In general, however, it is anticipated that the daily dose (whether administered as a single dose or as divided doses) will be in the range 0.01 to 1000 mg per day, more usually from 1 to 500 mg per day, and most usually from 10 to 200 mg per day. Expressed as dosage per unit body weight, a typical dose will be expected to be between 0.0001 mg/kg and 15 mg/kg, especially between 0.01 mg/kg and 7 mg/kg, and most especially between 0.15 mg/kg and 2.5 mg/kg.

The invention includes also pharmaceutically acceptable salts of the compounds represented by Formula (I), preferably of those described below. Pharmaceutically acceptable salts of the specific compounds exemplified herein are especially preferred.

In certain embodiments of compounds of Formula (I), R¹ is —H, —C₁₋₄alkyl, monocyclic cycloalkyl, phenyl, or benzyl. In certain embodiments, R¹ is —H, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —C(CH₃)₃, cyclopropyl, cyclobutyl, or benzyl. In further embodiments, R¹ is —H.

In certain embodiments of compounds of Formula (I), m has the value of 1, 2 or 3 and n has the value of 1 or 2; however, if m is 2 then n is not 1. In preferred embodiments, m is 1 and n is 1. In further embodiments, m is 1 and n is 2. In further embodiments, m is 2 and n is 2. In further embodiments, m is 3 and n is 1.

In certain embodiments of compounds of Formula (I), R² is —H or —C₁₋₄alkyl. In further embodiments, R² is —H, or —CH₃.

In certain embodiments of compounds of Formula (I), R³ is —H or —C₁₋₄alkyl. In further embodiments, R³ is —H, or —CH₃.

In certain embodiments of compounds of Formula (I), R² and R³ are each —H.

In certain embodiments of compounds of Formula (I), R⁴ is —H, F, —C₁₋₄alkyl or R⁴ may be —OH when L is —CH₂—, —CF₂—, —CHF—, —OCH₂—, or —OCH(CH₃)—In further embodiments, R⁴ is hydrogen.

In certain embodiments of compounds of Formula (I), L is —O—, —CH₂—, —OCH₂—, —OCH(CH₃)—, —CH₂O—, —CF₂—, or —CHF—. In certain embodiments, L is —O—.

In certain embodiments of compounds of Formula (I), Z is —O—, —C(O)—, —OCH(R^(b))—, or —OCH₂C(R^(c))(R^(d))—; where R^(b) is —H; a —C₁₋₄alkyl group unsubstituted or substituted with OH or halo; —CO₂C₁₋₄alkyl; or —CO₂H; and R^(c) and R^(d) are each independently —H, —C₁₋₄alkyl, —O—C₁₋₄alkyl, or halo. In certain embodiments of compounds of Formula (I), R^(c) and R^(d) taken together form an oxime, a C₁₋₄alkyl oxime, or a carbonyl group. In certain embodiments of compounds of Formula (I), R^(c) and R^(d) taken together with the carbon to which they are attached form a C₃₋₆cycloalkyl group. In certain embodiments of compounds of Formula (I), Z is —O—, —C(O)—, —OCH₂—, —OCH(CH₃)—, —OCH(CH₂CH₃)—, —OCH(CH₂OH)—, —OCH(CO₂H)—, —OCH(CH₂F)—, —OCH₂CH₂—, —OCH₂CH(F)—, —OCH₂CH(OCH₃)—, —OCH₂C(NOH)—, —OCH₂C(NOCH₃)—, —OCH₂CF₂—, —OCH₂C(O)—, or

In further embodiments, Z is —O—, —OCH₂—, or —OCH(CH₃)—.

In certain embodiments of compounds of Formula (I), R⁵ is a phenyl or phenoxy group, unsubstituted or substituted with one, two, or three R^(g) substituents; where each R^(g) substituent is selected from the group consisting of —C₁₋₆alkyl, —OH, —OC₁₋₆alkyl, —CN, —NO₂, —C(O)C₁₋₆alkyl, —S(O)₀₋₂—C₁₋₆alkyl, —OS(O)₀₋₂—C₁₋₆alkyl, —SO₂CF₃, —SCF₃, halo, —CF₃, —OCF₃, —CO₂H, —CO₂C₁₋₆alkyl, —CH₂OH, monocyclic cycloalkyl, phenyl, thiophenyl, benzhydryl, and oxadiazolyl. In further embodiments of compounds of Formula (I), two R^(g) substituents taken together form —OCH₂O—, —OCF₂O—, or —OCH₂CH₂O— group. In further embodiments, R⁵ is a naphthyl group, unsubstituted or substituted with C₁₋₄alkyl or halo. In further embodiments, R⁵ is a monocyclic heteroaryl group, unsubstituted or substituted with one, two, or three R^(g) substituents. In further embodiments, R⁵ is a fused bicyclic heteroaryl group, unsubstituted or substituted with C₁₋₄alkyl or halo. In further embodiments, R⁵ is a monocyclic cycloalkyl group, optionally fused to a phenyl ring, and unsubstituted or substituted with one or two substituents selected from the group consisting of: —C₁₋₄alkyl, —OC₁₋₄alkyl, halo, —CF₃, oxime, —C₁₋₄alkyl oxime, or phenyl. In further embodiments, R⁵ is a monocyclic heterocycloalkyl group, optionally fused to or substituted with phenyl. In further embodiments, R⁵ is cyclohexyl, 2-indanyl, or furanyl optionally substituted with one or more substituents individually selected from halo, —CH₃, —CF₃, —OCF₃, or —CN.

In certain embodiments, R⁵ is selected from the group consisting of cyclopropyl, cyclobutyl, 3-phenyl-cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 3- or 4-bromo-phenyl, 2-, 3- or 4-chloro-phenyl, 3,4-dichloro-phenyl, 3- or 4-cyano-phenyl, 2-, 3- or 4-fluoro-phenyl, 3-chloro-4-fluoro-phenyl, 4-chloro-3-fluoro-phenyl, 4-chloro-3-trifluoromethyl-phenyl, 3-chloro-4-trifluoromethoxy-phenyl, 2,4-difluoro-phenyl, 2-fluoro-4-trifluoromethyl-phenyl, 3-fluoro-4-trifluoromethyl-phenyl, 4-fluoro-3-trifluoromethyl-phenyl, 3- or 4-methyl-phenyl, 3- or 4-methylsulfanyl-phenyl, 3- or 4-methoxy-phenyl, 3-chloro-4-methoxy-phenyl, 3-methanesulfonyloxy-phenyl, 3- or 4-methoxy-phenyl, 3-trifluoromethoxy-phenyl, 2-, 3- or 4-trifluoromethyl-phenyl, 4-fluoro-3-trifluoromethyl-phenyl, 3- or 4-trifluoromethylsulfanyl-phenyl, 3-trifluoromethoxy-phenyl,

3-azetidinyl, 1-benzyl-azetidin-3-yl, 1-benzhydryl-azetidin-3-yl, 1-isopropyl-azetidin-3-yl, benzo[1,3]dioxol-5-yl, 2,2-difluoro-benzo[1,3]dioxol-5-yl, 2-benzofuranyl, 5-benzofuranyl, 2,3-dihydro-benzofuran-2-yl, 2-benzothiazolyl, 6-benzothiazolyl, 1H-benzotriazole-6-yl, 1-methyl-1H-benzotriazole-6-yl, 2- or 3-chromanyl, 2- or 3-furanyl, 5-trifluoromethyl-2-furanyl, 2-indanyl, tetrahydro-3-furanyl, 1-Hydroxyimino-indan-2-yl, 4-methoxy-2-indanyl, 5-fluoro-1-indanyl, 5-methyl-1-indanyl, 5- or 6-chloro-1-indanyl, 6-fluoro-1-indanyl, 6-trifluoromethyl-1-indanyl, 6-methyl-1-indanyl, 5-fluoro-2-indanyl, 5-methoxy-2-indanyl, [1,2,4]oxadiazole-5-yl, 3-cyclopropyl-[1,2,4]oxadiazole-5-yl, 3-cyclobutyl-[1,2,4]oxadiazole-5-yl, 3-isopropyl-[1,2,4]oxadiazole-5-yl, phenoxy, 4-piperidinyl, 2- or 3-pyrrolidinyl, 3-methyl-[1,2,4]oxadiazole-5-yl, 5-oxazolyl, 3-, 4- or 5-pyrazolyl, 4-trifluoromethyl-2-pyridinyl, 2-, 3- or 4-pyridinyl, 6-trifluoromethyl-2-pyridinyl, 1,2,3,4-tetrahydro-naphthalen-1-yl, 1,2,3,4-tetrahydro-naphthalen-2-yl, 1-phenyl-3-azetidinyl, 4- or 5-thiazolyl, 2-methyl-thiazole-4-yl, 2-thiophen-2-yl-thiazole-4-yl,

and 5-methyl-isoxazole-3-yl.

In certain embodiments of compounds of Formula (I), R⁶ and R⁷ are each independently —H, halo, —CF₃, thiophene, or —C(O)N(R^(x))R^(y); wherein R^(x) and R^(y) are each independently —H or —C₁₋₄alkyl. In certain embodiments of compounds of Formula (I), R⁶ and R⁷ are each independently —H, halo, —CF₃, thiophene-3-yl, or N,N-dimethyl-formamidyl. In certain embodiments, R⁶ is —H or halo. In certain embodiments, R⁶ is —H or halo and R⁷ is —H, halo, —CF₃, thiophene-3-yl, or N,N-dimethyl-formamidyl.

Preferred compounds are selected from the group consisting of:

EX. Chemical Name 1 3-(2-Benzyloxy-5-bromo-phenoxy)-azetidine; 2 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-azetidine; 3 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-cyclobutyl-azetidine; 4 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-propyl-azetidine; 5 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-isopropyl-azetidine; 6 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-ethyl-azetidine; 7 3-[5-Bromo-2-(3-trifluoromethoxy-benzyloxy)-phenoxy]-azetidine; 8 3-[5-Bromo-2-(3-trifluoromethyl-benzyloxy)-phenoxy]-azetidine; 9 3-[2-(Azetidin-3-yloxy)-4-bromo-phenoxymethyl]-benzonitrile; 10 3-[5-Bromo-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-azetidine; 11 3-[5-Bromo-2-(3-chloro-4-trifluoromethoxy-benzyloxy)-phenoxy]-azetidine; 12 3-[5-Bromo-2-(3-chloro-4-fluoro-benzyloxy)-phenoxy]-azetidine; 13 3-[5-Bromo-2-(3-chloro-4-methoxy-benzyloxy)-phenoxy]-azetidine; 14 3-[5-Bromo-2-(4-chloro-benzyloxy)-phenoxy]-azetidine; 15 3-[5-Bromo-2-(2-chloro-benzyloxy)-phenoxy]-azetidine; 16 3-[5-Bromo-2-(2-chloro-benzyloxy)-phenoxy]-1-methyl-azetidine; 17 3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-azetidine; 18 3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-ethyl-azetidine; 19 3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-propyl-azetidine; 20 3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-isopropyl-azetidine; 21 3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-cyclobutyl-azetidine 22 3-[4-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-azetidine; 23 3-[4-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-cyclobutyl-azetidine; 24 3-[4-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-isopropyl-azetidine; 25 3-[5-Chloro-2-(4-fluoro-benzyloxy)-phenoxy]-azetidine; 26 3-[5-Chloro-2-(3-methylsulfanyl-benzyloxy)-phenoxy]-azetidine; 27 3-[5-Chloro-2-(3-methanesulfonyl-benzyloxy)-phenoxy]-azetidine; 28 4-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-thiophen-2-yl-thiazole; 29 4-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-methyl-thiazole; 30 3-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-5-methyl-isoxazole; 31 3-[3-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-phenyl]-5-methyl- [1,2,4]oxadiazole; 32 3-[5-Chloro-2-(2-trifluoromethyl-benzyloxy)-phenoxy]-azetidine; 33 3-[5-Chloro-2-(3-methoxy-benzyloxy)-phenoxy]-azetidine; 34 3-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-benzonitrile; 35 3-[5-Chloro-2-(2-chloro-benzyloxy)-phenoxy]-azetidine; 36 3-[5-Chloro-2-(4-chloro-benzyloxy)-phenoxy]-azetidine; 37 3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-azetidine; 38 3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-azetidine; 39 3-[5-Chloro-2-(3-trifluoromethyl-benzyloxy)-phenoxy]-azetidine; 40 3-(2-Benzyloxy-5-chloro-phenoxy)-azetidine; 41 3-[5-Chloro-2-(3-chloro-4-trifluoromethoxy-benzyloxy)-phenoxy]-azetidine; 42 3-[5-Chloro-2-(4-trifluoromethoxy-benzyloxy)-phenoxy]-azetidine; 43 3-[5-Chloro-2-(4-trifluoromethyl-benzyloxy)-phenoxy]-azetidine; 44 4-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-benzonitrile; 45 3-[2-(2,4-Bis-trifluoromethyl-benzyloxy)-5-chloro-phenoxy]-azetidine; 46 3-[5-Chloro-2-(4-trifluoromethylsulfanyl-benzyloxy)-phenoxy]-azetidine; 47 3-[5-Chloro-2-(4-fluoro-3-trifluoromethyl-benzyloxy)-phenoxy]-azetidine; 48 3-[5-Chloro-2-(2-fluoro-4-trifluoromethyl-benzyloxy)-phenoxy]-azetidine; 49 3-[5-Chloro-2-(4-chloro-3-trifluoromethyl-benzyloxy)-phenoxy]-azetidine; 50 3-[5-Chloro-2-(3,4-dichloro-benzyloxy)-phenoxy]-azetidine; 51 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-pyridine; 52 3-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-pyridine; 53 4-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-pyridine; 54 3-[5-Chloro-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-azetidine; 55 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-furan-2-carboxylic acid ethyl ester; 56 3-[5-Chloro-2-(4-chloro-2-methanesulfonyl-benzyloxy)-phenoxy]-azetidine; 57 3-[5-Chloro-2-(2,4-difluoro-benzyloxy)-phenoxy]-azetidine; 58 (R)-3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine; 59 (R)-3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine; 60 (R)-3-[5-Chloro-2-(2-chloro-benzyloxy)-phenoxy]-pyrrolidine; 61 (R)-3-[5-Chloro-2-(2-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine; 62 4-(2-Benzyloxy-5-chloro-phenoxy)-piperidine; 63 4-[5-Chloro-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-piperidine; 64 4-[5-Bromo-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-piperidine; 65 4-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-piperidine; 66 4-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-piperidine; 67 4-[5-Bromo-2-(2-fluoro-benzyloxy)-phenoxy]-piperidine; 68 4-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-piperidine; 69 (±)-3-[5-Chloro-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-piperidine; 70 (±)-3-(2-Benzyloxy-5-chloro-phenoxy)-piperidine; 71 (±)-3-[5-Chloro-2-(3-trifluoromethyl-benzyloxy)-phenoxy]-piperidine; 72 3-(5-Chloro-2-cyclopentyloxy-phenoxy)-azetidine; 73 3-(5-Chloro-2-cyclohexylmethoxy-phenoxy)-azetidine; 74 3-(5-Bromo-2-cyclohexylmethoxy-phenoxy)-azetidine; 75 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-trifluoromethyl-furan-3- carboxylic acid; 76 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-trifluoromethyl-furan-3- carboxylic acid ethyl ester; 77 5-[4-Chloro-2-(1-methyl-azetidin-3-yloxy)-phenoxymethyl]-2-trifluoromethyl- furan-3-yl]-methanol; 78 3-[5-Chloro-2-(5-methyl-2-trifluoromethyl-furan-3-ylmethoxy)-phenoxy]- azetidine; 79 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-6-trifluoromethyl-pyridine; 80 3-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-methyl-6-trifluoromethyl- pyridine; 81 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-4-trifluoromethyl-pyridine; 82 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-trifluoromethyl-pyridine; 83 3-[2-(Benzofuran-5-ylmethoxy)-5-chloro-phenoxy]-azetidine; 84 6-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-benzothiazole; 85 6-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-1-methyl-1H-benzotriazole; 86 3-[5-Chloro-2-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethoxy)-phenoxy]- azetidine; 87 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-oxazole; 88 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-thiazole; 89 3-[2-(Benzofuran-2-ylmethoxy)-5-chloro-phenoxy]-azetidine; 90 (R)-3-(2-Benzyloxy-4-chloro-phenoxy)-pyrrolidine; 91 (R)-3-(2-Benzyloxy-4-chloro-phenoxy)-1-methyl-pyrrolidine; 92 (R)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine; 93 (R)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine; 94 (S)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine; 95 (±)-3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine; 96 (±)-3-[5-Bromo-2-(3-methoxy-benzyloxy)-phenoxy]-1-methyl-pyrrolidine; 97 (±)-3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine; 98 (±)-3-(2-Benzyloxy-5-bromo-phenoxy)-1-methyl-pyrrolidine; 99 (±)-Methanesulfonic acid 3-[4-bromo-2-(1-methyl-pyrrolidin-3-yloxy)- phenoxymethyl]-phenyl ester; 100 (±)-Methanesulfonic acid 3-[2-(1-methyl-pyrrolidin-3-yloxy)-phenoxymethyl]- phenyl ester; 101 (S)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine; 102 (S)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine; 103 (S)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-1-methyl- azetidine; 104 (S)-1-Benzyl-3-[5-chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]- azetidine; 105 (±)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine; 106 (±)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-1-isopropyl- azetidine; 107 (±)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-1-cyclobutyl- azetidine; 108 (±)-1-Benzyl-3-[5-chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]- azetidine; 109 (±)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-1-methyl- azetidine; 110 (±)-3-[5-Bromo-2-[1-(3-trifluoromethoxy-phenyl)-ethoxy]-phenoxy]-azetidine; 111 (±)-3-[5-Bromo-2-[1-(3-chloro-phenyl)-ethoxy]-phenoxy]-azetidine; 112 (±)-3-[5-Bromo-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine; 113 (R)-3-[5-Bromo-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine; 114 (±)-3-[5-Chloro-2-[1-(3-chloro-phenyl)-ethoxy]-phenoxy]-azetidine; 115 (±)-3-[5-Chloro-2-[1-(3-fluoro-phenyl)-ethoxy]-phenoxy]-azetidine; 116 (±)-3-[5-Chloro-2-[1-(2-chloro-phenyl)-ethoxy]-phenoxy]-azetidine; 117 (±)-3-[5-Chloro-2-[1-(4-fluoro-3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]- azetidine; 118 (±)-3-[5-Chloro-2-[1-(3-fluoro-4-trifluoromethyl-phenyl)-ethoxy]-phenoxy]- azetidine; 119 (±)-3-[5-Chloro-2-[1-(3-fluoro-5-trifluoromethyl-phenyl)-ethoxy]-phenoxy]- azetidine; 120 (±)-3-[5-Chloro-2-[1-(3-trifluoromethylsulfanyl-phenyl)-ethoxy]-phenoxy]- azetidine; 121 (±)-3-[5-Chloro-2-[1-(2-fluoro-phenyl)-ethoxy]-phenoxy]-azetidine; 122 (±)-3-[5-Chloro-2-[1-(2-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine; 123 (±)-3-[5-Chloro-2-[1-(4-chloro-phenyl)-ethoxy]-phenoxy]-azetidine; 124 (±)-3-[5-Chloro-2-[1-(4-fluoro-phenyl)-ethoxy]-phenoxy]-azetidine; 125 (±)-3-[1-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-ethyl]-benzonitrile; 126 (±)-3-[5-Chloro-2-[1-(3,4-dichloro-phenyl)-ethoxy]-phenoxy]-azetidine; 127 (±)-3-[5-Chloro-2-[1-(3-trifluoromethoxy-phenyl)-ethoxy]-phenoxy]-azetidine; 128 (±)-3-[5-Chloro-2-[1-(3,4-difluoro-phenyl)-ethoxy]-phenoxy]-azetidine; 129 (±)-3-[5-Chloro-2-[1-(2,5-dichloro-phenyl)-ethoxy]-phenoxy]-azetidine; 130 (±)-3-[5-Chloro-2-[1-(2,5-difluoro-phenyl)-ethoxy]-phenoxy]-azetidine; 131 2-[1-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-ethyl]-benzothiazole; 132 5-[1-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-ethyl]-thiazole; 133 2-[1-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-ethyl]-thiazole; 134 5-[1-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-ethyl]-2,4-dimethyl-thiazole; 135 (R)-4-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-piperidine; 136 (±)-4-[5-Chloro-2-[1-(3-chloro-phenyl)-ethoxy]-phenoxy]-piperidine; 137 (±)-4-[5-Chloro-2-[1-(3-trifluoromethoxy-phenyl)-ethoxy]-phenoxy]-piperidine; 138 (±)-4-[5-Chloro-2-[1-(2-fluoro-phenyl)-ethoxy]-phenoxy]-piperidine; 139 (R,S)-3-[5-Chloro-2-[1-((R)-3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]- piperidine; 140 (±)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-propoxy]-phenoxy]-azetidine; 141 (±)-4-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-propoxy]-phenoxy]-piperidine; 142 3-[5-Bromo-2-(2-fluoro-1-phenyl-ethoxy)-phenoxy]-azetidine; 143 3-[5-Chloro-2-(2-fluoro-1-phenyl-ethoxy)-phenoxy]-azetidine; 144 (±)-4-[5-Chloro-2-(2-fluoro-1-phenyl-ethoxy)-phenoxy]-piperidine; 145 (±)-3-[5-Chloro-2-(1-phenyl-ethoxy)-phenoxy]-azetidine; 146 (±)-3-[5-Chloro-2-[1-(5-trifluoromethyl-furan-2-yl)-ethoxy]-phenoxy]-azetidine; 147 3-[5-Chloro-2-(1-phenyl-propoxy)-phenoxy]-azetidine; 148 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-2-phenyl-ethanol; 149 [2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-phenyl-acetic acid; 150 (±)-3-[5-Chloro-2-(6-fluoro-indan-1-yloxy)-phenoxy]-azetidine; 151 (±)-3-[5-Bromo-2-(indan-1-yloxy)-phenoxy]-azetidine; 152 (±)-3-[5-Bromo-2-(5-chloro-indan-1-yloxy)-phenoxy]-azetidine; 153 (±)-3-[5-Bromo-2-(6-chloro-indan-1-yloxy)-phenoxy]-azetidine; 154 (±)-3-[5-Bromo-2-(5-fluoro-indan-1-yloxy)-phenoxy]-azetidine; 155 (±)-3-[5-Bromo-2-(5-methyl-indan-1-yloxy)-phenoxy]-azetidine; 156 (±)-3-[5-Bromo-2-(6-methyl-indan-1-yloxy)-phenoxy]-azetidine; 157 (±)-3-[5-Bromo-2-(6-trifluoromethyl-indan-1-yloxy)-phenoxy]-azetidine; 158 (±)-3-[5-Chloro-2-(6-methyl-indan-1-yloxy)-phenoxy]-azetidine; 159 (±)-3-[5-Chloro-2-(6-chloro-indan-1-yloxy)-phenoxy]-azetidine; 160 3-[5-Chloro-2-(6-trifluoromethyl-indan-1-yloxy)-phenoxy]-azetidine; 161 3-[5-Chloro-2-(1,2,3,4-tetrahydro-naphthalen-1-yloxy)-phenoxy]-azetidine; 162 3-[5-Bromo-2-(5-tert-butyl-indan-1-yloxy)-phenoxy]-azetidine; 163 3-[5-Chloro-2-(tetrahydro-furan-3-ylmethoxy)-phenoxy]-azetidine; 164 3-[5-Chloro-2-(1,2,3,4-tetrahydro-naphthalen-2-yloxy)-phenoxy]-azetidine; 165 3-[5-Chloro-2-(chroman-2-ylmethoxy)-phenoxy]-azetidine; 166 3-[5-Chloro-2-(tetrahydro-furan-2-ylmethoxy)-phenoxy]-azetidine; 167 3-[5-Chloro-2-(chroman-3-ylmethoxy)-phenoxy]-azetidine; 168 3-[5-Chloro-2-(2-methoxy-2-phenyl-ethoxy)-phenoxy]-azetidine; 169 3-[5-Chloro-2-(2,3-dihydro-benzofuran-2-ylmethoxy)-phenoxy]-azetidine; 170 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-1,3-dimethyl-1H-pyrazole; 171 3-[5-Chloro-2-(2-phenoxy-ethoxy)-phenoxy]-azetidine; 172 3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-phenyl-azetidine; 173 3-[5-Chloro-2-(indan-2-yloxy)-phenoxy]-azetidine; 174 3-[5-Bromo-2-(indan-2-yloxy)-phenoxy]-azetidine; 175 3-[5-Chloro-2-(5-fluoro-indan-2-yloxy)-phenoxy]-azetidine; 176 3-[5-Chloro-2-(5-chloro-indan-2-yloxy)-phenoxy]-azetidine; 177 3-[5-Chloro-2-(5-methoxy-indan-2-yloxy)-phenoxy]-azetidine; 178 3-[5-Chloro-2-(4-methoxy-indan-2-yloxy)-phenoxy]-azetidine; 179 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-indan-1-one oxime; 180 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-indan-1-one O-methyl-oxime; 181 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-1-phenyl-ethanone oxime; 182 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-1-phenyl-ethanone O-methyl- oxime; 183 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-1-(4-chloro-phenyl)-ethanone; 184 3-[5-Chloro-2-(2,2-difluoro-2-phenyl-ethoxy)-phenoxy]-azetidine; 185 3-[5-Chloro-2-[2-(3-chloro-phenyl)-ethoxy]-phenoxy]-azetidine; 186 3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-azetidine; 187 3-[5-Chloro-2-(2-fluoro-2-phenyl-ethoxy)-phenoxy]-azetidine; 188 3-[5-Chloro-2-[1-(4-chloro-phenyl)-cyclobutylmethoxy]-phenoxy]-azetidine; 189 3-[5-Chloro-2-[1-(3-chloro-phenyl)-cyclobutylmethoxy]-phenoxy]-azetidine; 190 3-[5-Chloro-2-[2-(3-methoxy-phenyl)-ethoxy]-phenoxy]-azetidine; 191 3-[5-Chloro-2-[2-(3-fluoro-phenyl)-ethoxy]-phenoxy]-azetidine; 192 3-[5-Chloro-2-[2-(4-chloro-phenyl)-ethoxy]-phenoxy]-azetidine; 193 3-[5-Chloro-2-[2-(4-fluoro-phenyl)-ethoxy]-phenoxy]-azetidine; 194 3-[5-Chloro-2-[2-(4-methoxy-phenyl)-ethoxy]-phenoxy]-azetidine; 195 3-(5-Bromo-2-phenethyloxy-phenoxy)-azetidine; 196 3-(Azetidin-3-yloxy)-2-benzyloxy-5-chloro-pyridine; 197 3-(2-Benzyloxy-5-chloro-3-fluoro-phenoxy)-azetidine; 198 3-[5-Chloro-3-fluoro-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]- azetidine; 199 3-[5-Trifluoromethyl-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]- azetidine; 200 3-[5-Trifluoromethyl-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]- azetidine; 201 3-[2-(1-Phenyl-ethoxy)-5-trifluoromethyl-phenoxy]-azetidine; 202 3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-azetidine; 203 3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-1-methyl-azetidine; 204 3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-1-isopropyl-azetidine; 205 3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-1-cyclobutyl-azetidine; 206 3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-1-propyl-azetidine; 207 3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-1-ethyl-azetidine; 208 3-[5-Fluoro-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-azetidine; ; 209 3-[5-Fluoro-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-1-isopropyl- azetidine; 210 3-[2-(3-Chloro-benzyloxy)-5-thiophen-3-yl-phenoxy]-azetidine; 211 3-(Azetidin-3-yloxy)-4-(3-chloro-benzyloxy)-N,N-dimethyl-benzamide; 212 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-3-methyl-azetidine; 213 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-3-ethyl-azetidine; 214 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-3-isopropyl-azetidine; 215 3-(5-Bromo-2-phenethyloxy-phenoxy)-3-methyl-azetidine; 216 3-[5-Bromo-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-azetidine; 217 3-[5-Bromo-2-(3-trifluoromethyl-benzyloxy)-phenoxy]-azetidine; 218 3-(5-Bromo-2-phenoxy-phenoxy)-3-methyl-azetidine; 219 (±)-trans-3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-2-methyl-azetidine; 220 cis-1-Benzyl-3-[5-bromo-2-(3-fluoro-benzyloxy)-phenoxy]-2-methyl-azetidine; 221 trans-1-Benzyl-3-[5-bromo-2-(3-fluoro-benzyloxy)-phenoxy]-2-methyl- azetidine; 222 3-[5-Chloro-2-(1-phenyl-azetidin-3-ol)-phenoxy]-azetidine; 223 (±)-3-[5-Chloro-2-(trans-1-benzyl-2-methyl-azetidin-3-ol)-phenoxy]-azetidine; 224 3-[5-Chloro-2-(1-Isopropyl-azetidin-3-ol)-phenoxy]-azetidine; 225 3-[5-Chloro-2-(1-benzhydryl-azetidin-3-ol)-phenoxy]-azetidine; 226 3-[5-Chloro-2-(1-azetidin-3-ol)-phenoxy]-azetidine; 227 3-[5-Chloro-2-(1-Isopropyl-azetidin-3-ol)-phenoxy]-1-isopropyl-azetidine; 228 3-[5-Chloro-2-(3-phenyl-cyclobutoxy)-phenoxy]-azetidine; 229 3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-tert-butyl-azetidine; 230 1-tert-Butyl-3-[5-chloro-2-(3-trifluoromethyl-benzyloxy)-phenoxy]-azetidine 231 1-tert-Butyl-3-[5-chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]- azetidine; 232 3-[5-Bromo-2-(5-trifluoromethyl-furan-2-ylmethoxy)-benzyl]-azetidine; 233 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxymethyl]-azetidine; 234 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxymethyl]-1-methyl-azetidine; 235 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxymethyl]-azetidin-3-ol; 236 3-[1-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-ethyl]-azetidin-3-ol; 237 3-[5-Bromo-2-(3-chloro-benzyloxy)-benzyloxy]-azetidine; 238 3-[5-Chloro-2-(3-chloro-benzyloxy)-benzyloxy]-azetidine; 239 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-3-methyl-[1,2,4]oxadiazole; 240 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-3-cyclobutyl- [1,2,4]oxadiazole; 241 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-3-cyclopropyl- [1,2,4]oxadiazole; 242 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-3-isopropyl- [1,2,4]oxadiazole; 243 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-3-ethyl-[1,2,4]oxadiazole; 244 3-(5-Bromo-2-phenoxy-phenoxy)-azetidine; 245 3-[5-Bromo-2-(3-bromo-phenoxy)-phenoxy]-azetidine; 246 3-[5-Bromo-2-(3-fluoro-phenoxy)-phenoxy]-azetidine; 247 3-(5-Bromo-2-m-tolyloxy-phenoxy)-azetidine; 248 3-[5-Bromo-2-(3-methoxy-phenoxy)-phenoxy]-azetidine; 249 3-[5-Bromo-2-(4-fluoro-phenoxy)-phenoxy]-azetidine; 250 3-[5-Bromo-2-(4-bromo-phenoxy)-phenoxy]-azetidine; 251 3-[5-Bromo-2-(4-chloro-phenoxy)-phenoxy]-azetidine; 252 3-[5-Bromo-2-(3-chloro-phenoxy)-phenoxy]-azetidine; 253 3-[5-Bromo-2-(3-trifluoromethoxy-phenoxy)-phenoxy]-azetidine; 254 3-[5-Bromo-2-(naphthalen-2-yloxy)-phenoxy]-azetidine; 255 3-[5-Bromo-2-(naphthalen-1-yloxy)-phenoxy]-azetidine; 256 3-(5-Chloro-2-phenoxy-phenoxy)-azetidine; 257 3-[5-Chloro-2-(3-chloro-phenoxy)-phenoxy]-azetidine; 258 3-[5-Chloro-2-(4-chloro-phenoxy)-phenoxy]-azetidine; 259 3-(5-Chloro-2-o-tolyloxy-phenoxy)-azetidine; 260 3-[5-Chloro-2-(naphthalen-2-yloxy)-phenoxy]-azetidine; 261 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-benzothiazole; 262 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-benzooxazole; 263 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-[1,8]naphthyridine; 264 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-quinoline; 265 4-(5-Chloro-2-phenoxy-phenoxy)-piperidine; 266 (S)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-pyrrolidine; 267 (R)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-pyrrolidine; 268 (R)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-1-methyl-pyrrolidine; 269 (S)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-pyrrolidine; 270 (R)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-pyrrolidine; 271 (R)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-1-methyl-pyrrolidine; 272 (S)-3-(4-Chloro-2-o-tolyloxy-phenoxy)-pyrrolidine; 273 (S)-3-(4-Chloro-2-m-tolyloxy-phenoxy)-pyrrolidine; 274 (S)-3-[4-Chloro-2-(4-fluoro-3-methyl-phenoxy)-phenoxy]-pyrrolidine; 275 (S)-3-[4-Chloro-2-(4-chloro-phenoxy)-phenoxy]-pyrrolidine; 276 (S)-3-[4-Chloro-2-(3-chloro-phenoxy)-phenoxy]-pyrrolidine; 277 (S)-3-[2-(4-Bromo-phenoxy)-4-chloro-phenoxy]-pyrrolidine; 278 (S)-3-[4-Chloro-2-(4-isopropyl-phenoxy)-phenoxy]-pyrrolidine; 279 (±)-3-[5-Bromo-2-(4-bromo-phenoxy)-phenoxy]-1-ethyl-pyrrolidine; 280 2-(Azetidin-3-yloxy)-4-bromo-phenyl]-phenyl-methanone; 281 [2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(4-chloro-phenyl)-methanone; 282 [2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(3-chloro-phenyl)-methanone; 283 [4-Bromo-2-(1-methyl-azetidin-3-yloxy)-phenyl]-(3-chloro-phenyl)- methanone; 284 [2-(Azetidin-3-yloxy)-4-bromo-phenyl]-m-tolyl-methanone; 285 [2-(Azetidin-3-yloxy)-4-bromo-phenyl]-o-tolyl-methanone; 286 [2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(3-methoxy-phenyl)-methanone; 287 [2-(Azetidin-3-yloxy)-4-bromo-phenyl]-naphthalen-2-yl-methanone; 288 [4-Bromo-2-(1-isopropyl-azetidin-3-yloxy)-phenyl]-naphthalen-2-yl- methanone; 289 [2-(Azetidin-3-yloxy)-4-bromo-phenyl]-benzo[1,3]dioxol-5-yl-methanone; 290 Benzo[1,3]dioxol-5-yl-[4-bromo-2-(1-isopropyl-azetidin-3-yloxy)-phenyl]- methanone; 291 [2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(4-methoxy-phenyl)-methanone; 292 [2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(4-chloro-3-fluoro-phenyl)-methanone; 293 [2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(3,4-dichloro-phenyl)-methanone; 294 [2-(Azetidin-3-yloxy)-4-chloro-phenyl]-naphthalen-2-yl-methanone; 295 [2-(Azetidin-3-yloxy)-4-chloro-phenyl]-benzo[1,3]dioxol-5-yl-methanone; 296 Benzo[1,3]dioxol-5-yl-[4-chloro-2-(1-isopropyl-azetidin-3-yloxy)-phenyl]- methanone; 297 [2-(Azetidin-3-yloxy)-4-chloro-phenyl]-(4-chloro-phenyl)-methanone; and 298 [2-(Azetidin-3-yloxy)-4-chloro-phenyl]-(3-chloro-phenyl)-methanone; and stereoisomeric forms, hydrates, solvates, pharmaceutically acceptable salts, prodrugs, and active metabolites thereof.

Exemplary chemical entities useful in methods of the invention will now be described by reference to illustrative synthetic schemes for their general preparation below and the specific examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Unless otherwise specified, the variables in the formulas depicted in the schemes below are as defined above in reference to Formula (I). Reactions may be performed between the melting point and the reflux temperature of the solvent, and preferably between 0° C. and the reflux temperature of the solvent.

List of abbreviations: Ac=Acetyl, AIBN=azobisisobutyronitrile, Boc=tert-Butylcarbamoyl, m-CPBA=meta-chloroperoxybenzoic acid, DCE=dichloroethane, DEAD=diethyldiazodicarboxylate, DIBAL-H=diisobutyl aluminum hydride, DIEA=N,N-Diisopropylethylamine, DMA=N,N-Dimethylacetamide, DME=Ethylene glycol dimethyl ether, DMF=dimethylformamide, DMSO=Dimethyl sulfoxide, Et₃N=triethylamine, Et₂O=diethyl ether, EtOAc=Ethyl acetate, MeCN=acetonitrile, MeOH=methanol, MsCI=Methanesulfonyl chloride, TFA=trifluoroacetic acid, TFAA=trifluoroacetic acid anhydride, THF=tetrahydrofuran, TLC=thin layer chromatography, Q-Phos=1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene.

The compounds of formula (I) may be prepared by a number of reaction schemes. The following schemes represent certain synthesis steps for obtaining compounds of the invention. Persons skilled in the art will recognize that certain compounds are more advantageously produced by one scheme as compared to the other.

The amines in the compounds below may be protected, as indicated by P¹, as an alkyl or benzyl amine, amide, carbamate or other groups such as described in “Protecting Groups in Organic Synthesis”, 3^(rd) ed.; T. W. Greene and P. G. Wuts, John Wiley and Sons, 1999. Preferably, P¹ is —C₁₋₆Alkyl, —COOC₁₋₆Alkyl, —(C═O)C₁₋₆Alkyl, benzyl substituted or unsubstituted with —OC₁₋₆Alkyl or C₁₋₆Alkyl, or benzhydryl substituted or unsubstituted with —OC₁₋₆Alkyl or —C₁₋₆Alkyl). A further preferred protecting group is t-butyl carbamate (Boc) or trifluoroacetamide. This protecting group (P¹) on the nitrogen may be removed or converted directly into the desired compounds using generally accepted methods known to one skilled in the art. More specifically a group such as a Boc group may be removed with an acid such as trifluoroacetic acid or hydrochloric acid and the like in a solvent such as CH₂Cl₂, EtOAc, THF, 1,4-dioxane, MeOH or EtOH. A group such as trifluoroacetamide was removed using a base such as NH₃, NH₄OH or K₂CO₃ in an alcoholic solvent such as MeOH or EtOH and the like.

Intermediates of the formula A5 were prepared according to Scheme A. The variable Z in the formula depicted in Scheme 1 are as defined above in reference to Formula (I) except Z cannot be —C(O)— in Scheme 1. Compounds of the formula A1 were treated with tert-butylamine in the presence of a dehydrating agent such as SiO₂, CuSO₄, Ti(OiPr)₄, MgSO₄ or molecular sieves in a suitable solvent such as THF, CH₂Cl₂, benzene, toluene, MeOH or EtOH. A preferred method uses MgSO₄ in CH₂Cl₂ to give compounds of the formula A2. Compounds of the formula A2 were allowed to react with compounds of the formula A3 in a suitable solvent such as DMF, DMSO, NMP or THF in the presence of a base such as NaH, KOtBu or Cs₂CO₃, preferably NaH in DMF, to produce compounds of formula A4. Compounds of the formula A5 were obtained from compounds of the formula A4 upon basic hydrolysis of the compound obtained from the treatment of compounds of the formula A4 with an oxidant such as m-chloroperoxybenzoic acid (m-CPBA) in CH₂Cl₂. The hydrolysis is performed using a base such as NaOH or KOH in a solvent such as MeOH, EtOH or H₂O.

Intermediates of the formula A4 were alternatively prepared according to Scheme B. Compounds of the formula A4 were alternatively obtained from compounds of the formula B1, where LG represents a chloride, bromide, iodide, mesylate or tosylate, upon treatment with a compound of the formula B2. The variable Z in the formulas depicted in Scheme 2 are as defined above in reference to Formula (I) except Z cannot be —C(O)— in Scheme 2. This type of reaction was carried out in a solvent such as DMF, DMA, THF or EtOH in the presence of bases such as NaHCO₃, Na₂CO₃, K₂CO₃ or Cs₂CO₃. Alternatively, compounds of the formula A4 may also be obtained from compounds of the formula B1 when LG is OH using PPh₃ or similar trialkyl or triaryl phosphine and diethyldiazodicarboxylate (DEAD), diisopropyldiazodicarboxylate (DIAD) or di-tert-butyldiazodicarboxylate (DBAD) in a solvent such as MeCN, DMF, THF or CH₂Cl₂ and the like. One skilled in the art will recognize this as a Mitsunobu reaction.

Intermediates of the formula C3 were prepared according to Scheme C. Compounds of the formula C3 were synthesized similar to compounds of the formula A5 (Scheme 1) from compounds of the formula C1. Compounds of the formula C2 were obtained from compounds of the formula C1 and compounds of the formula A2 (Scheme 1) in a suitable solvent such as DMF, DMSO, NMP or THF in the presence of a base such as NaH, KOtBu or Cs₂CO₃, preferably NaH in DMF. Compounds of the formula C3 were obtained from compounds of the formula C2 upon basic hydrolysis of the compound obtained from the treatment of compounds of the formula C2 with an oxidant such as m-chloroperoxybenzoic acid (m-CPBA) in CH₂Cl₂. The hydrolysis was performed using a base such as NaOH or KOH in a solvent such as MeOH, EtOH or H₂O.

Intermediates of the formula C2 were alternatively prepared according to Scheme D using compounds of the formula D1. The amine in compounds of the formula C2 may be protected with a protecting group, as indicated by P¹, with previously described protecting groups. Treatment of compounds of formula D1 with a nucleophile such as a compound of formula B2 (Scheme 2) in the presence of base such as pyridine, triethylamine, diisopropylamine, K₂CO₃, Cs₂CO₃ or Na₂CO₃ in a suitable solvent such as THF, CH₂Cl₂, DMF, MeCN, 1,4-dioxane or the like at a temperature ranging from rt to 100° C. provided compounds of the formula C2. Compounds of the formula D1 were obtained from compounds of the formula C1 when treated with methanesulfonyl chloride (MsCl) in the presence of a base such as pyridine, triethylamine or diisopropylamine and the like in a solvent such as CH₂Cl₂, THF or DCE.

Intermediates of the formula E2 were prepared according to Scheme E. Compounds of the formula E2 were obtained after addition of compounds of the formula E2 to compounds of the formula E1. One skilled in the art will recognize compounds of the formula E2 as Grignard reagents.

Intermediates of the formula F4 were prepared according to Scheme F. Compounds of the formula F4 were prepared from compounds of the formula F2, where LG represents a Cl or Br, and F3. Compounds of the formula F2 were prepared from compounds of the formula F1 upon treatment with an oxidizing agent such as m-CPBA in a solvent such as CH₂Cl₂.

Intermediates of the formula G7 were prepared according to Scheme G. Compounds of the formula G3 were synthesized from compounds of the formula G1 and compounds of the formula G2 using solvents such as Et₂O, THF, CH₂Cl₂, or dioxane and the like. One skilled in the art will recognize G1 as a Weinreb amide (Nahm, S. et al., Tet. Lett., 1981, 22, 3815-3818) and G2 as a Grignard reagent. Compounds of the formula G4 were obtained from compounds of the formula G3 by partial reduction with hydride donors such as NaBH₄ in alcoholic solvents such as MeOH, EtOH or i-PrOH and the like followed by further reduction using H₂ in the presence of a hydrogenation catalyst such as Pd/C, PtO₂ or Pd(OH)₂ and the like at pressures up to 60 psi and temperatures ranging from rt to 60° C. in solvents such as MeOH, EtOH or i-PrOH and the like. The Boc protecting group in compounds of the formula G2 was exchanged for a trifluoroacetamide as shown in compounds of the formula G5 by treatment with acids such as trifluoroacetic acid or hydrochloric acid and the like in a solvent such as CH₂Cl₂, EtOAc, THF, 1,4-dioxane, MeOH or EtOH. Treatment of the intermediate from this reaction with trifluoroacetic anhydride (TFAA) in the presence of a base such as pyridine, triethylamine or diisopropylethylamine or the like in a solvent such as CH₂Cl₂, THF, DMF, MeOH, EtOH or the like yields compounds of the formula G5. Treatment of compounds of the formula G5 with an electrophilic bromine source such as Br₂, NBS, NaBr/oxone or chlorine source such as Cl₂, KCl/oxone or NCS and the like in a solvent such as MeOH, CH₂Cl₂, EtOH, DMF, acetone, H₂O and the like or mixtures there of produces compounds of the formula G6. Treatment of compounds of the formula G6 with a reagent such as LiI in collidine, HBr in AcOH, or preferrably BBr₃ in CH₂Cl₂, produces compounds of the formula G7.

Intermediates of the formula H6 were prepared according to Scheme H. Compounds of the formula H3 were obtained from compounds of the formula C3 upon treatment with compounds of the formula H1, representing an alkyl chloride, bromide, iodide, mesylate or tosylate in a solvent such as DMF, DMA, THF or EtOH in the presence of bases such as NaHCO₃, Na₂CO₃, K₂CO₃ or Cs₂CO₃. Alternatively, compounds of the formula H3 may also be obtained from compounds of the formula H2 when X is OH using PPh₃ or similar trialkyl or triaryl phosphine and diethyldiazodicarboxylate (DEAD), diisopropyldiazodicarboxylate (DIAD) or di-tert-butyldiazodicarboxylate (DBAD) in a solvent such as MeCN, DMF, THF or CH₂Cl₂ and the like. One skilled in the art will recognize this as a Mitsunobu reaction. The transformation when X is OH may also be performed using cyanomethylene-tri-n-butylphosphine in a solvent such as PhCH₃ when heated in a microwave reactor at temperatures up to 120° C. When R₅ is a substituted aryl or heteroaryl, compounds of the formula H3 were obtained using Cu(OAc)₂ and base such as pyridine or Et₃N and the like in the presence of dehydrating agents such as MgSO₄ or 4 Å molecular sieves.

Compounds such as H6 were prepared from compounds of the formula H4 using methods such as reductive amination or alkylation. Thus treatment of H4 with a compound of formula H5 containing a carbonyl in the presence of a reductant such as NaBH₄, NaBH₃CN, NaBH(OAc)₃ or hydrogen gas in the presence of a catalyst in a solvent such as CH₂Cl₂, THF, DCE, MeOH, EtOH or similar afforded compounds of the formula H6. One skilled in the art will recognize that the presence of Bronsted or Lewis acids may be required. Examples of acids may include AcOH, Ti(O-iPr)₄, trifluoroacetic acid or hydrochloric acid and the like. One skilled in the art will also recognize that compounds of the formula H6 may be obtained from H4 upon treatment with an alkyl chloride, bromide, iodide, mesylate or tosylate and the like in a solvent such as DMF, DMA, THF or EtOH in the presence of bases such as NaHCO₃, Na₂CO₃, K₂CO₃ or Cs₂CO₃. It will be generally recognized that compounds of the formula H6 represent a subset of compounds of the formula H4 where R₁ is equal to H. Compounds of the formula H4 or H6 may be converted to their corresponding salts using methods generally accepted to those skilled in the art.

Intermediates of the formula H1 were prepared according to Scheme I when not commercially available.

Intermediates of the formula J4 were prepared according to Scheme J. Compounds of the formula J4 were prepared from compounds of the formula J1 and compounds of the formula J3 (prepared as in Scheme A) using cyanomethylene-tri-n-butylphosphine in a solvent such as PhCH₃ when heated in a microwave reactor at temperatures up to 120° C. In this reaction scheme, the preferred protecting group, P¹ is a benzhydryl group. Alternatively, compounds of the formula J4 were also synthesized from compounds of the formula D1 (Scheme D). Treatment of a compound of formula D1 with a nucleophile such as a compound of formula J3 in the presence of base such as pyridine, triethylamine, diisopropylamine, K₂CO₃, Cs₂CO₃ or Na₂CO₃ in a suitable solvent such as THF, CH₂Cl₂, DMF, MeCN, 1,4-dioxane or the like at a temperature ranging from rt to 100° C. provided compounds of the formula J4.

Intermediates of the formula K4 were prepared according to Scheme K. The variable R^(n) in the formulas depicted in Scheme K are —H or —C₁₋₄alkyl. The variable Z in the formulas depicted in Scheme K are as defined above in reference to Formula (I) except Z cannot be —C(O)— in Scheme K. Compounds of the formula K2 were obtained from compounds of the formula K1 and compounds of the formula A4 in the presence of cyanomethylene-tri-n-butylphosphine in a solvent such as PhCH₃ when heated in a microwave reactor at temperatures up to 120° C. Alternatively, when the protecting group on nitrogen was a benzhydryl as in compounds of the formula K3 compounds of the formula K4 were obtained using similar conditions.

Intermediates of the formula L4 were prepared according to Scheme L. The variable Z in the formulas depicted in Scheme L are as defined above in reference to Formula (I) except Z cannot be —C(O)— in Scheme L. The amine in compounds of the formula L3 may be protected, as indicated by P¹, as discussed previously. Compounds of the formula L3 were prepared from compounds of the formula L2 and compounds of the formula C1 in the presence of base such as pyridine, triethylamine, diisopropylamine, K₂CO₃, Cs₂CO₃ or Na₂CO₃ in a suitable solvent such as THF, CH₂Cl₂, DMF, MeCN, 1,4-dioxane or the like at a temperature ranging from rt to 100° C. Compounds of the formula L2 were prepared from compounds of the formula L1 by treatment with a chlorinating agent such as SOCl₂ in a solvent such as CH₂Cl₂. Compounds of the formula L1 were prepared from compounds of the formula A4 using a reducing agent such as NaBH₄, LiBH₄, Dibal-H, LiAlH₄ and the like in a solvent such as CH₂Cl₂, THF, DCE, MeOH or EtOH and the like.

Intermediates of the formula M5 were prepared according to Scheme M. The variable Z in the formulas depicted in Scheme M are as defined above in reference to Formula (I) except Z cannot be —C(O)— in Scheme M. Compounds of the formula M4 may be prepared from compounds of the formula M3 and compounds of the formula C1 using a base such as NaH and the like in a solvent such as THF, DMF, NMP or DMSO at temperatures up to 145° C. in a microwave reactor. Compounds of the formula M3 may be prepared from compounds of the formula M1 and compounds of the formula M2 using a base such as NaH and the like in a solvent such as THF, DMF, NMP or DMSO and the like.

Compounds of the formula M5 may be obtained from compounds of the formula M4 by removal of the P¹ group. The amine in compounds of the formula M4 may be protected, as indicated by P¹, as described previously. A preferred protecting group is t-butyl carbamate (Boc) or trifluoroacetamide. It will be generally recognized that compounds of the formula M5 may be converted to their corresponding salts using methods generally accepted to those skilled in the art.

Intermediates of the formula N5 were prepared according to Scheme N. Compounds of the formula N5 may be obtained from compounds of the formula N4 by removal of the P¹ group. The amine in compounds of the formula N4 may be protected, as indicated by P¹, as described previously. A preferred protecting group is t-butyl carbamate (Boc) or trifluoroacetamide. It will be generally recognized that compounds of the formula N5 may be converted to their corresponding salts using methods generally accepted to those skilled in the art.

Compounds of the formula N4 were prepared from compounds of the formula N2 and compounds of the formula N3 in the presence of a base such as diisopropyethylamine, Et₃N or pyridine and the like upon heating in a microwave reactor at temperatures up to 145° C. Precursors to compounds of the formula N2 were prepared from compounds of the formula N1 and bromomethyl acetate in a solvent such as DMF, DMA, THF or EtOH in the presence of bases such as NaHCO₃, Na₂CO₃, K₂CO₃ or Cs₂CO₃. Subsequent hydrolysis using aqueous NaOH followed by formation of compounds of the formula N2 using oxalyl chloride in a solvent such as THF, CH₂Cl₂ or PhCH₃ in the presence of a catalytic amount of DMF provided compounds of the formula N2.

Intermediates of the formula O6 were prepared according to Scheme O. The amine in compounds of the formula O5 may be protected, as indicated by P¹ as described previously. A preferred protecting group is t-butyl carbamate (Boc) or trifluoroacetamide. Compounds of the formula O6 were obtained from compounds of the formula O5 by removal of the P¹ group. It will be generally recognized that compounds of the formula O6 may be converted to their corresponding salts using methods generally accepted to those skilled in the art.

Compounds of the formula O5 were prepared form compounds of the formula O3 and compounds of the formula O4 using a base such as NaHCO₃, Na₂CO₃, K₂CO₃ or Cs₂CO₃ in solvents such as MeOH, EtOH or iPrOH. Compounds of the formula O3 were prepared from compounds of the formula C3 and compounds of the formula O2 by heating the mixture up to 100° C. in a microwave reactor in a solvent such as DMF, DMA, THF or EtOH in the presence of bases such as NaHCO₃, Na₂CO₃, K₂CO₃ or Cs₂CO₃. Compounds of the formula O2 were obtained by bromination of compounds of the formula O1 using (Bu)N₄Br₃ (TBABr₃) in a solvent mixture of MeOH and CH₂Cl₂.

Intermediates of the formula P1 were prepared according to Scheme P. Compounds of the formula P1 were synthesized from compounds of the formula O3 using a hydride donor such as Et₃SiH in the presence of an acid such as trifluoroacetic acid in a solvent such as DCE or CH₂Cl₂.

Intermediates of the formula Q5 were prepared according to Scheme Q. Compounds of the formula Q3 were prepared from compounds of the formula Q2 by oxidation with an oxidant such as the Dess-Martin periodinane in a solvent such as CH₂Cl₂. Compounds of the formula Q2 were prepared from compounds of the formula C2 (Scheme C) and compounds of the formula Q1 in solvents such as Et₂O, THF, CH₂Cl₂, or dioxane and the like.

Compounds of the formula Q4 may be obtained from compounds of the formula Q3 by removal of the P¹ group. The amine in compounds of the formula Q3 may be protected, as indicated by P¹ as described previously. A preferred protecting group is t-butyl carbamate (Boc) or trifluoroacetamide. It will be generally recognized that compounds of the formula Q4 represent a subset of compounds of the formula Q5 where R₆ is equal to H. Compounds of the formula Q4 or Q5 may be converted to their corresponding salts using methods generally accepted to those skilled in the art.

Compounds such as Q5 were prepared from compounds of the formula Q4 using methods such as reductive amination or alkylation. Thus treatment of Q4 with a compound containing a carbonyl in the presence of a reductant such as NaBH₄, NaBH₃CN, NaBH(OAc)₃ or hydrogen gas in the presence of a catalyst in a solvent such as CH₂Cl₂, THF, DCE, MeOH, EtOH or similar afforded compounds of the formula Q5. One skilled in the art will recognize that the presence of Bronsted or Lewis acids may be required. Examples of acids may include AcOH, Ti(O-iPr)₄, trifluoroacetic acid or hydrochloric acid and the like. One skilled in the art will also recognize that compounds of the formula Q5 may be obtained from Q4 upon treatment with an alkyl chloride, bromide, iodide, mesylate or tosylate and the like in a solvent such as DMF, DMA, THF or EtOH in the presence of bases such as NaHCO₃, Na₂CO₃, K₂CO₃ or Cs₂CO₃.

Intermediates of the formula R3 were prepared according to Scheme R. Compounds of the formula R2 were synthesized from compounds of the formula R1 (prepared as outlined in Scheme G) using an oxidant such as m-CPBA in a solvent such as CH₂Cl₂. Compounds of the formula R3 may be obtained from compounds of the formula R2 by removal of the P¹ group. The amine in compounds of the formula R2 may be protected, as indicated by P¹ as described previously. A preferred protecting group is t-butyl carbamate (Boc) or trifluoroacetamide.

Intermediates of the formula S4 were prepared according to Scheme S. Compounds of the formula S2 were obtained from compounds of the formula S1 by bromination using NBS in the presence of AIBN in solvents such as CCl₄ at refluxing temperatures. Compounds of the formula S3 were obtained from compounds of the formula N1 and compounds of the formula S2 in a solvent such as DMF, DMA, THF or EtOH in the presence of bases such as NaHCO₃, Na₂CO₃, K₂CO₃ or Cs₂CO₃ followed by a work-up with neutral H₂O. A preferred protecting group on compounds of the formula N1 was Boc.

Intermediates of the formula T2 were prepared according to Scheme T. Compounds of the formula T1 were obtained from compounds of the formula N1 and compounds of the formula S2 in a solvent such as DMF, DMA, THF or EtOH in the presence of bases such as NaHCO₃, Na₂CO₃, K₂CO₃ or Cs₂CO₃ followed by a work-up with basic H₂O where the pH was >10. A preferred protecting group on compounds of the formula N1 was Boc.

Intermediates of the formula U2 were prepared according to Scheme U. Compounds of the formula U2 were prepared from compounds of the formula U1 using reducing agents such as Dibal-H in solvents such as CH₂Cl₂, THF or PhCH₃ and the like.

Intermediates of the formula V3 were prepared according to Scheme V. Compounds of the formula V2 were prepared from compounds of the formula V1 using reducing agents such as LiBH₄ and the like in solvents such as CH₂Cl₂, THF or PhCH₃ and the like. Compounds of the formula V3 were prepared from compounds of the formula V2 using acids such as trifluoroacetic acid or hydrochloric acid and the like in a solvent such as CH₂Cl₂, EtOAc, THF, 1,4-dioxane, MeOH or EtOH.

Intermediates of the formula W2 were prepared according to Scheme W. Compounds of the formula W1 were prepared from compounds of the formula V1 by hydrolysis using aqueous hydroxide bases such as NaOH or KOH and the like with an organic co-solvent such as THF or MeOH. A preferred protecting group on compounds of the formula V1 was Boc.

Intermediates of the formula X4 were prepared according to Scheme X. A preferred protecting group on compounds of the formula X1 was Boc. Compounds of the formula X3, were prepared from compounds of the formula X1 and compounds of the formula X2 by heating in a microwave reactor at temperatures up to 170° C. in the presence of Hermann's catalyst, Mo(CO)₆ and bases such as Na₂CO₃ and the like.

Intermediates of the formula Y3 were prepared according to Scheme Y. A preferred protecting group on compounds of the formula X1 was Boc. Compounds of the formula Y2, were prepared from compounds of the formula X1 by treatment with compounds of the formula Y1 in the presence of a catalyst such as PdCl₂(dppf), PdCl₂(dppe) Pd₂(dba)₃, Pd(dba)₂, PdCl₂(PPh₃)₂, Pd(PPh₃)₄ in a solvent such as PhCH₃, 1,4-dioxane, THF, DMA, DMF or DME in the presence of a base such as Na₂CO₃, K₂CO₃, Cs₂CO₃, CsF, KF, K₃PO₄, KOAc or the like and a ligand typically used in such reactions such as Q-Phos, dppf, dppe or PPh₃ and the like at temperatures ranging from rt to 160° C. using conventional or microwave heating.

EXAMPLES

Chemistry

In obtaining the compounds described in the examples below and the corresponding analytical data, the following experimental and analytical protocols were followed unless otherwise indicated.

Unless otherwise stated, reaction mixtures were magnetically stirred at room temperature (rt). Where solutions were “dried,” they were generally dried over a drying agent such as Na₂SO₄ or MgSO₄ then filtered and concentrated. Where mixtures, solutions, and extracts were “concentrated”, they were typically concentrated on a rotary evaporator under reduced pressure.

Thin-layer chromatography (TLC) was performed using Merck silica gel 60 F₂₅₄ 2.5 cm×7.5 cm 250 μm or 5.0 cm×10.0 cm 250 μm pre-coated silica gel plates. Preparative thin-layer chromatography (PTLC) was performed using EM Science silica gel 60 F₂₅₄ 20 cm×20 cm 0.5 mm pre-coated plates with a 20 cm×4 cm concentrating zone.

Normal-phase flash column chromatography (FCC) was performed on silica gel (SiO₂) eluting with 2M NH₃ in MeOH/CH₂Cl₂ or EtOAc in hexanes, unless otherwise noted.

Preparative reversed-phase HPLC (RP HPLC) was performed on a Hewlett Packard HPLC Series 1100, with a Phenomenex Luna C18 (5 μm, 4.6×150 mm) column. Detection was done at 2=230, 254 and 280 nm. The gradient was 10 to 99% acetonitrile/H₂O (0.05% trifluoroacetic acid) over 5.0 min with a flow rate of 1 mL/min. Alternatively, HPLC was performed on a Dionex APS2000 LC/MS with a Phenomenex Gemini C18 (5 μm, 30×100 mm) column, and a gradient of 5 to 100% acetonitrile/H₂O (20 mM NH₄OH) over 16.3 min, and a flow rate of 30 mL/min. Preparative RP HPLC was also performed on an Agilent 1100 preparative system with a Waters X-Bridge C18 (5 μm, 30×100 mm) column, and a gradient of 5 to 99% acetonitrile/H₂O (20 mM NH₄OH) over 17 min, and a flow rate of 80 mL/min.

Mass spectra (MS) were obtained on an Agilent series 1100 MSD using electrospray ionization (ESI) in positive mode unless otherwise indicated. Calculated (calcd.) mass corresponds to the exact mass.

Nuclear magnetic resonance (NMR) spectra were obtained on Bruker model DRX spectrometers. The format of the ¹H NMR data below is: chemical shift in ppm downfield of the tetramethylsilane reference or relative to residual protic solvent (multiplicity, coupling constant J in Hz, integration).

Chemical names were generated using ChemDraw Version 6.0.2 (CambridgeSoft, Cambridge, Mass.).

General Procedures

General Procedure 1 (Removal of Boc Qroups):

Boc groups were deprotected using TFA/CH₂Cl₂ (1:1) or 4M HCl in dioxane/EtOAc (1:1). The compounds were then either neutralized and extracted with CH₂Cl₂ or characterized as the hydrochloride or trifluoroacetate salt where indicated.

General Procedure 2 (Removal of Trifluroacetamide Groups):

Trifluoroacetamide groups were deprotected using K₂CO₃ (1 eq.) in MeOH (0.2M), 2M NH₃ in MeOH or 5N NH₄OH (aq.) in MeOH. After 15 h, H₂O was added and the mixture extracted with EtOAc (2×). The combined organics were dried and concentrated. Purification using silica gel chromatoraphy, reverse-phase HPLC or PTLC then provided the deprotected amines.

General Procedure 3 (Reductive Amination):

To amine in CH₂Cl₂ (0.1M) was added ketone (1.2-5.0 eq.) and NaBH(OAc)₃ (1.2 eq.). After 18 h, the reaction was typically treated with 5% Na₂CO₃ (aq.) and extracted with CH₂Cl₂ (2×). The combined organics were dried and purified using silica gel chromatography, reverse-phase HPLC or PTLC.

General Procedure 4 (Reductive Amination):

To amine in MeOH (0.1M) was added ketone or aldehyde (1.2-5.0 eq.), AcOH (10 mol %) and NaCNBH₃ (1.2 eq.). After 18 h, the reaction was typically treated with 5% Na₂CO₃ (aq.) and extracted with CH₂Cl₂ (2×). The combined organics were dried and purified using silica gel chromatography, reverse-phase HPLC or PTLC.

General Procedure 5 (NH to NMe):

To amine in MeOH (0.1M) was added excess 37 wt % [H₂CO]n in H₂O and NaBHOAc₃ (1.2 eq.). After 18 h, 5% Na₂CO₃ (aq.) was added and the mixture extracted with CH₂Cl₂. The combined organics were dried and purified using silica gel chromatography, reverse-phase HPLC or PTLC to yield the corresponding methylated analogs.

General Procedure 6 (Cu(OAc)2-Mediated Diaryl Ether Synthesis):

To a phenol in DCE (0.1M) was added arylboronic acid (2 eq.), Cu(OAc)₂ (1 eq.), MgSO₄ (2 eq) or 4 Å molecular sieves and Et₃N (5 eq). The reactions were allowed to stir open to the air for 12-48 h, then filtered, concentrated and purified using silica gel chromatography, reverse-phase HPLC or PTLC.

General Procedure 7 (Mitsunobu Reaction):

To phenol (1 eq), alcohol (1 eq) and either PPh₃ (1.2 eq) or resin-bound PPh₃ in THF (0.2M) at 0° C. or rt was added DEAD (1.1 eq) dropwise. After judged complete, the reactions were concentrated and purified using silica gel chromatography, reverse phase HPLC or PTLC.

Example 1: 3-(2-Benzyloxy-5-bromo-phenoxy)-azetidine

Step A: Preparation of (4-bromo-2-fluoro-benzylidene)-tert-butyl-amine

To a CH₂Cl₂ (900 mL) solution of 4-bromo-2-fluoro-benzaldehyde (50.0 g, 246 mmol) was added tert-butylamine (42.3 mL, 29.3 g, 400 mmol) and MgSO₄ (60.0 g, 499 mmol). After 48 h, the solution was filtered and concentrated to give 62.0 g (98%) of the title compound as a yellow liquid. ¹H NMR (CDCl₃): 8.48 (s, 1H), 7.89 (t, J=8.1 Hz, 1H), 7.32-7.25 (m, 2H), 1.29 (s, 9H).

Step B: Preparation of 3-(5-bromo-2-formyl-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester

To a 0° C. DMF (720 mL) solution of the title compound of Step A (37.2 g, 144 mmol) and 3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (25.0 g, 144 mmol) was added NaH (60 wt % in mineral oil, 7.50 g, 188 mmol) portionwise over 2 h. The reaction was then allowed to warm to rt. After 18 h, H₂O was added and the reaction mixture was extracted with EtOAc (2×). The combined organic layers were washed with brine and concentrated to give a yellow liquid that was treated with THF (360 mL), H₂O (360 mL) and AcOH (25 mL). After 5 h, this solution was made basic with 5% Na₂CO₃ (aq.) and extracted with EtOAc (2×). The combined organic layers were washed with brine and dried. The resulting solid was then triturated with 20% EtOAc in hexanes to give 41.9 g (82%) of the title compound as a white solid. ¹H NMR (CDCl₃): 10.43 (s, 1H), 7.74 (d, J=8.3 Hz, 1H), 7.26-7.23 (m, 1H), 6.77 (d, J=1.6 Hz, 1H), 5.01-4.95 (m, 1H), 4.39 (ddd, J=9.9, 6.3, 0.8 Hz, 2H), 4.08 (dd, J=6.4, 0.8 Hz, 2H), 1.46 (s, 9H).

Step C: Preparation of 3-(5-Bromo-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester

To a CH₂Cl₂ (280 mL) solution of the title compound of Step B (24.7 g, 69.4 mmol) was added 77% m-CPBA (23.3 g, 104 mmol). After 15 h, 10% Na₂S₂O₅ (aq.) was added and the solution allowed to stir until the aqueous was KI paper negative then extracted with CH₂Cl₂ (2×). The combined organic layers were washed with saturated NaHCO₃ (aq.), concentrated and treated with MeOH (220 mL) and 1N NaOH (220 mL). After 15 h, the reaction was partially concentrated to remove the MeOH, acidified with 1M KHSO₄ (220 mL) and extracted with CH₂Cl₂ (2×). The combined organic layers were washed with brine and dried providing a brown solid that was triturated with EtOAc/hexanes giving 17.6 g (74%) of the title compound as a white solid. ¹H NMR (CDCl₃): 7.03 (dd, J=8.5, 2.1 Hz, 1H), 6.84 (d, J=8.5 Hz, 1H), 6.64 (d, J=2.2 Hz, 1H), 4.93-4.89 (m, 1H), 4.34 (dd, J=10.1, 6.8 Hz, 1H), 4.03 (dd, J=9.9, 3.7 Hz, 1H), 1.46 (s, 9H).

Step D: Preparation of 3-(2-benzyloxy-5-bromo-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester

To a DMF (10 mL) solution of the title compound of Step C (0.52 g, 1.5 mmol), Cs₂CO₃ (0.54 g, 1.7 mmol) and KI (0.20 g, 1.20 mmol) was added benzyl bromide (0.20 mL, 0.29 g, 1.7 mmol). After 48 h, H₂O was added and the mixture extracted with EtOAc (2×). The combined organics were washed with brine (2×) and dried. Silica gel chromatography (5-20% EtOAc in hexanes) gave 0.65 g (99%) of the title compound as a clear oil. ¹H NMR (CDCl₃): 7.42-7.36 (m, 3H), 7.34-7.31 (m, 2H), 7.03 (dd, J=8.6, 2.3 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 6.70 (d, J=2.3 Hz, 1H), 5.09 (s, 2H), 4.88-4.83 (m, 1H), 4.26 (ddd, J=9.7, 6.5, 0.9 Hz, 2H), 4.05 (dd, J=9.8, 4.0 Hz, 2H), 1.45 (s, 9H).

Step E: Preparation of 3-(2-Benzyloxy-5-bromo-phenoxy)-azetidine

Synthesized according to general procedure 1 from the title compound of Step D. MS (ESI): mass calcd. for C₁₆H₁₆BrNO₂, 333.0; m/z found, 334.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.08 (dd, J=8.6, 2.3 Hz, 1H), 6.77 (d, J=8.6 Hz, 1H), 6.67 (d, J=2.2 Hz, 1H), 4.86 (tt, J=6.5, 4.3 Hz, 1H), 4.29 (ddd, J=9.7, 6.5, 0.8 Hz, 2H), 4.08 (dd, J=10.1, 4.2 Hz, 2H), 3.85 (s, 3H), 1.44 (s, 9H).

Unless otherwise specified the compounds in Examples 2-74 were prepared similar to Example 1 using the appropriately substituted phenol and alkyl halide.

Example 2: 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₆H₁₅BrClNO₂, 367.0; m/z found, 368.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.47-7.43 (m, 1H), 7.31-7.27 (m, 3H), 7.00 (dd, J=8.6, 2.3 Hz, 1H), 6.78-6.73 (m, 2H), 5.06 (s, 2H), 5.01-4.95 (m, 1H), 3.94-3.83 (m, 4H).

The compounds in Examples 3-6 were prepared from the title compound of Example 2 using general procedure 3 or 4.

Example 3: 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-cyclobutyl-azetidine

MS (ESI): mass calcd. for C₂₀H₂₁BrClNO₂, 422.7; m/z found, 423.9 [M+H]⁺. ¹H NMR (CDCl₃): 7.43 (s, 1H), 7.32-7.26 (m, 3H), 6.98 (dd, J=8.5, 2.3 Hz, 1H), 6.75 (dd, J=13.6, 5.4 Hz, 2H), 5.05 (s, 2H), 4.77-4.72 (m, 1H), 3.78-3.65 (m, 2H), 3.12-3.16 (m, 3H), 2.01-1.95 (m, 2H), 1.87-1.79 (m, 2H), 1.78-1.69 (m, 2H).

Example 4: 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-propyl-azetidine

MS (ESI): mass calcd. for C₁₉H₂₁BrClNO₂, 410.7; m/z found, 411.9 [M+H]⁺. ¹H NMR (CDCl₃): 7.44 (s, 1H), 7.33-7.27 (m, 3H), 7.02-6.95 (m, 1H), 6.76 (dd, J=13.4, 5.4 Hz, 2H), 5.06 (s, 2H), 4.78-4.74 (m, 1H), 3.88-3.80 (m, 2H), 3.14-3.06 (m, 2H), 2.52-2.44 (m, 2H), 1.45-1.34 (m, 2H), 0.91 (t, J=7.4 Hz, 3H).

Example 5: 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-isopropyl-azetidine

MS (ESI): mass calcd. for C₁₉H₂₁BrClNO₂, 410.7; m/z found, 411.9 [M+H]⁺. ¹H NMR (CDCl₃): 7.44 (s, 1H), 7.32-7.27 (m, 3H), 6.99 (dd, J=8.6, 2.3 Hz, 1H), 6.79 (d, J=2.3 Hz, 1H), 6.75 (d, J=8.6 Hz, 1H), 4.98 (s, 2H), 4.75-4.70 (m, 1H), 3.88-3.71 (m, 2H), 3.15-2.94 (m, 2H), 2.43-2.38 (m, 1H), 0.99-0.95 (m, 6H).

Example 6: 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-ethyl-azetidine

MS (ESI): mass calcd. for C₁₈H₁₉BrClNO₂, 396.7; m/z found, 397.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.44 (d, J=1.8, 1H), 7.35-7.26 (m, 3H), 6.99 (dd, J=8.6, 2.3 Hz, 1H), 6.76 (dd, J=14.8, 5.4 Hz, 2H), 5.06 (s, 2H), 4.78-4.73 (m, 1H), 3.873.79 (m, 2H), 3.11-3.08 (m, 2H), 2.55 (q, J=7.2, 2H), 1.00 (t, J=7.2 Hz, 3H).

Example 7: 3-[5-Bromo-2-(3-trifluoromethoxy-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₅BrF₃NO₃, 417.0; m/z found, 418.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.40 (t, J=8.1 Hz, 1H), 7.34-7.33 (m, 2H), 7.18-7.16 (m, 1H), 7.00 (dd, J=8.6, 2.3 Hz, 1H), 6.77 (d, J=8.6 Hz, 1H), 6.73 (d, J=2.3 Hz, 1H), 5.10 (s, 2H), 5.01-4.96 (m, 1H), 3.93-3.86 (m, 4H).

Example 8: 3-[5-Bromo-2-(3-trifluoromethyl-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₅BrF₃NO₂, 401.0; m/z found, 401.9 [M+H]⁺. ¹H NMR (CDCl₃): 7.75 (s, 1H), 7.60 (t, J=7.2 Hz, 2H), 7.51 (t, J=7.7 Hz, 1H), 7.02 (dd, J=8.6, 2.3 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 6.74 (d, J=2.3 Hz, 1H), 5.14 (s, 2H), 5.01-4.95 (m, 1H), 3.93-3.86 (m, 4H).

Example 9: 3-[2-(Azetidin-3-yloxy)-4-bromo-phenoxymethyl]-benzonitrile

¹H NMR (CDCl₃): 7.78 (s, 1H), 7.67-7.61 (m, 2H), 7.50 (t, J=7.7 Hz, 1H), 7.01 (dd, J=8.6, 2.3 Hz, 1H), 6.76 (d, J=8.6 Hz, 1H), 6.73 (d, J=2.3 Hz, 1H), 5.12 (s, 2H), 5.02-4.96 (m, 1H), 3.95-3.86 (m, 4H).

Example 10: 3-[5-Bromo-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₅H₁₃BrF₃NO₃, 391.0; m/z found, 392.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.03 (dd, J=8.6, 2.3 Hz, 1H), 6.84 (d, J=8.6 Hz, 1H), 6.79-6.76 (m, 1H), 6.74 (d, J=2.3 Hz, 1H), 6.47 (d, J=3.3 Hz, 1H), 5.06 (s, 2H), 5.00-4.93 (m, 1H), 3.96-3.89 (m, 2H), 3.88-3.79 (m, 2H).

Example 11: 3-[5-Bromo-2-(3-chloro-4-trifluoromethoxy-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₄BrClF₃NO₃, 451.0; m/z found, 452.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.62-7.59 (m, 2H), 7.35-7.32 (m, 2H), 7.02 (dd, J=8.6, 2.3 Hz, 1H), 6.78 (d, J=8.6 Hz, 1H), 6.74 (d, J=2.3 Hz, 1H), 5.06 (s, 2H), 5.03-4.96 (m, 1H), 3.98-3.91 (m, 2H), 3.89-3.83 (m, 2H).

Example 12: 3-[5-Bromo-2-(3-chloro-4-fluoro-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₆H₁₄BrClFNO₂, 385.0; m/z found, 386.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.52 (dd, J=7.0, 2.1 Hz, 1H), 7.31-7.25 (m, 1H), 7.15 (dd, J=8.7, 8.6 Hz, 1H), 7.01 (dd, J=8.6, 2.3 Hz, 1H), 6.77 (d, J=8.6 Hz, 1H), 6.73 (d, J=2.3 Hz, 1H), 5.03 (s, 2H), 5.01-4.95 (m, 1H), 3.99-3.91 (m, 2H), 3.90-3.81 (m, 2H).

Example 13: 3-[5-Bromo-2-(3-chloro-4-methoxy-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₇BrClNO₃, 397.0; m/z found, 398.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.48 (d, J=2.1 Hz, 1H), 7.29-7.25 (m, 1H), 7.02 (dd, J=8.6, 2.3 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.79 (d, J=8.6 Hz, 1H), 6.73 (d, J=2.3 Hz, 1H), 5.01 (s, 2H), 5.00-4.94 (m, 1H), 3.96-3.83 (m, 4H), 3.92 (s, 3H).

Example 14: 3-[5-Bromo-2-(4-chloro-benzyloxy)-phenoxy]-azetidine trifluoroacetate

MS (ESI): mass calcd. for C₁₆H₁₅BrClNO₂, 367.00; m/z found, 368.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.41-7.30 (m, 4H), 7.12 (dd, J=8.7, 2.3 Hz, 1H), 6.87 (d, J=2.3 Hz, 1H), 6.80 (d, J=8.7 Hz, 1H), 5.06-4.99 (m, 3H), 4.31-4.13 (m, 4H).

Example 15: 3-[5-Bromo-2-(2-chloro-benzyloxy)-phenoxy]-azetidine trifluoroacetate

MS (ESI): mass calcd. for C₁₆H₁₅BrClNO₂, 367.0; m/z found, 368.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.46 (dd, J=5.5, 3.8 Hz, 1H), 7.41 (dd, J=5.6, 3.7 Hz, 1H), 7.32-7.27 (m, 2H), 7.13 (dd, J=8.7, 2.2 Hz, 1H), 6.89 (d, J=2.3 Hz, 1H), 6.83 (d, J=8.7 Hz, 1H), 5.14 (s, 2H), 5.07-4.99 (m, 1H), 4.26-4.21 (m, 4H).

Example 16: 3-[5-Bromo-2-(2-chloro-benzyloxy)-phenoxy]-1-methyl-azetidine

Synthesized from the title compound of Example 15 according to general procedure 5. MS (ESI): mass calcd. for C₁₇H₁₇BrClNO₂, 381.0; m/z found, 382.1 [M+H]⁺. ¹H NMR (CDC₃): 7.59-7.51 (m, 1H), 7.39 (dd, J=7.4, 1.7 Hz, 1H), 7.32-7.23 (m, 2H), 7.00 (dd, J=8.6, 2.3 Hz, 1H), 6.78 (dd, J=5.4, 3.1 Hz, 2H), 5.19 (s, 2H), 4.78-4.73 (m, 1H), 3.92-3.78 (m, 2H), 3.21-3.11 (m, 2H), 2.42 (s, 3H).

Example 17: 3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-azetidine trifluroacetate

MS (ESI): mass calcd. for C₁₆H₁₅BrFNO₂, 351.0; m/z found, 352.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.36 (dt, J=7.9, 5.9 Hz, 1H), 7.16 (d, J=7.6 Hz, 1H), 7.13-7.08 (m, 2H), 7.03 (dt, J=8.4, 2.1 Hz, 1H), 6.86 (d, J=2.2 Hz, 1H), 6.80 (d, J=8.7 Hz, 1H), 5.04 (s, 3H), 4.29-4.22 (m, 4H).

The compounds in Examples 18-21 were prepared from the title compound of Example 17 using general procedure 3 or 4.

Example 18: 3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-ethyl-azetidine

MS (ESI): mass calcd. for C₁₈H₁₉BrFNO₂, 380.3; m/z found, 381.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.35-7.31 (m, 1H), 7.17-7.15 (m, 2H), 7.00-6.97 (m, 2H), 6.76 (dd, J=16.1, 5.4 Hz, 2H), 5.08 (s, 2H), 4.78-4.74 (m, 1H), 3.85-3.82 (m, 2H), 3.13-3.05 (m, 2H), 2.57-2.53 (m, 2H), 1.00 (t, J=7.2 Hz, 3H).

Example 19: 3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-propyl-azetidine

MS (ESI): mass calcd. for C₁₉H₂₁BrFNO₂, 394.3; m/z found, 395.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.34-7.21 (m, 1H), 7.15-7.13 (m, 2H), 7.02-6.92 (m, 2H), 6.74 (dd, J=14.8, 5.4 Hz, 2H), 5.06 (s, 2H), 4.76-4.72 (m, 1H), 3.85-3.77 (m, 2H), 3.11-3.04 (m, 2H), 2.46 (dd, J=8.8, 6.0 Hz, 2H), 1.43-1.32 (m, 2H), 0.89 (t, J=7.4 Hz, 3H).

Example 20: 3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-isopropyl-azetidine

MS (ESI): mass calcd. for C₁₉H₂₁BrFNO₂, 394.3; m/z found, 395.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.34-7.30 (m, 1H), 7.18-7.12 (m, 2H), 7.02-6.94 (m, 2H), 6.80-6.71 (m, 2H), 5.07 (s, 2H), 4.74-4.69 (m, 1H), 3.85-3.78 (m, 2H), 3.12-3.06 (m, 2H), 2.43-2.36 (m, 1H), 0.96 (d, J=6.2 Hz, 6H).

Example 21: 3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-cyclobutyl-azetidine

MS (ESI): mass calcd. for C₂₀H₂₁BrFNO₂, 406.3; m/z found, 407.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.34-7.30 (m, 1H), 7.19-7.09 (m, 2H), 7.04-6.87 (m, 2H), 6.75 (dd, J=14.4, 5.4 Hz, 2H), 5.07 (s, 2H), 4.77-4.72 (m, 1H), 3.82-3.57 (m, 2H), 3.28-2.99 (m, 3H), 2.03-1.92 (m, 2H), 1.88-1.78 (m, 2H), 1.77-1.70 (m, 2H).

Example 22: 3-[4-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₆H₁₅BrClNO₂, 368.7; m/z found, 369.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.47 (s, 1H), 7.33-7.29 (m, 3H), 7.06-6.99 (m, 2H), 6.50 (d, J=8.4 Hz, 1H), 5.07 (s, 2H), 5.00-4.93 (m, 1H), 3.94-3.82 (m, 4H).

Example 23: 3-[4-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-cyclobutyl-azetidine

Synthesized from the title compound of Example 22 according to general procedure 3. MS (ESI): mass calcd. for C₂₀H₂₁BrClNO₂, 422.7; m/z found, 423.9 [M+H]⁺. ¹H NMR (CDCl₃): 7.46-7.41 (m, 1H), 7.35-7.25 (m, 3H), 7.03-6.95 (m, 2H), 6.53 (d, J=8.6 Hz, 1H), 5.03 (s, 2H), 4.76-4.70 (m, 1H), 3.73-3.65 (m, 2H), 3.22-3.10 (m, 3H), 2.02-1.90 (m, 2H), 1.88-1.57 (m, 4H).

Example 24: 3-[4-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-isopropyl-azetidine

Synthesized from the title compound of Example 22 according to general procedure 3. MS (ESI): mass calcd. for C₁₉H₂₁BrClNO₂, 410.7; m/z found, 412.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.45 (s, 1H), 7.34-7.22 (m, 3H), 7.04-6.99 (m, 2H), 6.59-6.53 (m, 1H), 5.04 (s, 2H), 4.74-4.68 (m, 1H), 3.83-3.76 (m, 2H), 3.11-3.04 (m, 2H), 2.43-2.34 (m, 1H), 0.99-0.90 (m, 6H).

Example 25: 3-[5-Chloro-2-(4-fluoro-benzyloxy)-phenoxy]-azetidine hydrochloride

MS (ESI): mass calcd. for C₁₆H₁₅ClFNO₂, 307.1; m/z found, 308.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 9.37 (s, 2H), 7.51 (dd, J=8.7, 5.6 Hz, 2H), 7.23 (t, J=8.9 Hz, 2H), 7.1 (d, J=8.7 Hz, 1H), 7.03 (dd, J=8.7, 2.4 Hz, 1H), 6.92 (d, J=2.4 Hz, 1H), 5.11 (s, 2H), 5.08-5.02 (m, 1H), 4.37 (dd, J=12.5, 6.7 Hz, 2H), 3.98 (dd, J=12.5, 5.0 Hz, 2H).

Example 26: 3-[5-Chloro-2-(3-methylsulfanyl-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₈ClNO₂S, 335.1; m/z found, 336.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.33-7.29 (m, 2H), 7.18 (dd, J=13.3, 7.8 Hz, 2H), 6.86-6.81 (m, 2H), 6.59 (d, J=2.1 Hz, 1H), 5.07 (s, 2H), 5.01-4.95 (m, 1H), 3.94-3.84 (m, 4H), 2.49 (2, 3H).

Example 27: 3-[5-Chloro-2-(3-methanesulfonyl-benzyloxy)-phenoxy]-azetidine

Step A: Preparation of 3-[5-Chloro-2-(3-methanesulfonyl-benzyloxy)-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester

To the title compound of Example 26 (0.050 g, 0.10 mmol) in CH₂Cl₂ (1 mL) was added 77% m-CPBA (0.06 g, 0.25 mmol). After 18 h, 10% Na₂S₂O₅ (aq.) was added and the mixture extracted with CH₂Cl₂ (2×). The combined organics were dried. Silica gel chromatography gave 0.038 g (80%) of the title compound as a clear oil. MS (ESI): mass calcd. for C₂₂H₂₆ClNO₆S, 467.1; m/z found, 368.1 [M−100]⁺, 490.1 [M+Na]⁺. ¹H NMR (CDCl₃): 8.03 (s, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.62 (t, J=7.8 Hz, 1H), 6.91 (dd, J=8.6, 2.3 Hz, 1H), 6.86 (d, J=8.6 Hz, 1H), 6.57 (d, J=2.3 Hz, 1H), 5.17 (s, 2H), 4.91-4.85 (m, 1H), 4.31 (dd, J=10.4, 6.4 Hz, 2H), 4.08-4.03 (m, 2H), 3.08 (s, 3H), 1.45 (s, 9H).

Step B: Preparation of 3-[5-Chloro-2-(3-methanesulfonyl-benzyloxy)-phenoxy]-azetidine

Prepared from the title compound of Step A using general procedure 1. MS (ESI): mass calcd. for C₁₇H₁₈ClNO₄S, 367.1; m/z found, 368.0 [M+H]⁺. ¹H NMR (CDCl₃): 8.10 (s, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.73 (d, J=7.7 Hz, 1H), 7.60 (t, J=7.8 Hz, 1H), 6.89-6.83 (m, 2H), 6.60 (d, J=2.1 Hz, 1H), 5.17 (s, 2H), 5.03-4.97 (m, 1H), 3.97-3.85 (m, 4H), 3.07 (s, 3H).

Example 28: 4-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-thiophen-2-yl-thiazole

MS (ESI): mass calcd. for C₁₇H₁₅ClN₂O₂S₂, 378.0; m/z found, 379.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.52 (dd, J=3.7, 0.9 Hz, 1H), 7.40 (dd, J=5.0, 0.9 Hz, 1H), 7.25 (m, 1H), 7.08 (dd, J=5.0, 3.7 Hz, 1H), 6.92-6.86 (m, 2H), 6.60 (d, J=2.3 Hz, 1H), 5.25 (s, 2H), 5.01-4.97 (m, 1H), 3.95-3.85 (m, 4H).

Example 29: 4-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-methyl-thiazole

MS (ESI): mass calcd. for C₁₇H₁₅ClN₂O₂S, 310.1; m/z found, 311.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.15 (d, J=10.2 Hz, 1H), 6.95-6.85 (m, 2H), 6.59 (d, J=2.1 Hz, 1H), 5.18 (d, J=0.8 Hz, 2H), 5.00-4.95 (m, 1H), 3.93-3.87 (m, 4H), 2.73 (s, 3H).

Example 30: 3-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-5-methyl-isoxazole

MS (ESI): mass calcd. for C₁₄H₁₅ClN₂O₃, 294.1; m/z found, 295.2 [M+H]⁺. ¹H NMR (CDCl₃): 6.90 (d, J=8.6 Hz, 1H), 6.85 (dd, J=8.6, 2.3 Hz, 1H), 6.58 (d, J=2.3 Hz, 1H), 6.13 (s, 1H), 5.14 (s, 2H), 4.99-4.94 (m, 1H), 3.96-3.89 (m, 2H), 3.87-3.80 (m, 2H), 2.43 (s, 3H).

Example 31: 3-[3-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-phenyl]-5-methyl-[1,2,4]oxadiazole hydrochloride

MS (ESI): mass calcd. for C₁₉H₁₈ClN₃O₃, 371.1; m/z found, 372.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 9.22 (s, 2H), 8.10 (s, 1H), 7.95 (d, J=7.7 Hz, 1H), 7.65 (d, J=7.7 Hz, 1H), 7.59 (t, J=7.7 Hz, 1H), 7.13 (d, J=8.7 Hz, 1H), 7.03 (dd, J=8.7, 2.4 Hz, 1H), 6.93 (d, J=2.4 Hz, 1H), 5.24 (s, 2H), 5.09-5.05 (m, 1H), 4.41 (dd, J=12.5, 6.7 Hz, 2H), 4.02 (dd, J=12.3, 4.9 Hz, 2H), 2.67 (s, 3H).

Example 32: 3-[5-Chloro-2-(2-trifluoromethyl-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₅ClF₃NO₂, 357.1; m/z found, 358.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.79 (d, J=7.8 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.57 (t, J=7.6, 1H), 7.41 (t, J=7.6 Hz, 1H), 6.85 (dd, J=8.6, 2.3 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 6.61 (d, J=2.3 Hz, 1H), 5.30 (s, 2H), 5.03-4.97 (m, 1H), 3.96-3.85 (m, 4H).

Example 33: 3-[5-Chloro-2-(3-methoxy-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₈ClNO₃, 319.1; m/z found, 320.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.31-7.22 (m, 1H), 7.00-6.95 (m, 2H), 6.86-6.78 (m, 3H), 6.58 (d, J=2.1 Hz, 1H), 5.07 (s, 2H), 4.99-4.94 (m, 1H), 3.94-3.82 (m, 4H), 3.80 (s, 3H).

Example 34: 3-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-benzonitrile

MS (ESI): mass calcd. for C₁₇H₁₅ClN₂O₂, 314.1; m/z found, 315.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.78 (s, 1H), 7.66 (d, J=7.8 Hz, 1H), 7.62 (d, J=7.7 Hz, 1H), 7.49 (t, J=7.8 Hz, 1H), 6.86 (dd, J=8.6, 2.3 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 6.60 (d, J=2.3 Hz, 1H), 5.11 (s, 2H), 5.04-4.99 (m, 1H), 3.98-3.91 (m, 2H), 3.89-3.81 (m, 2H).

Example 35: 3-[5-Chloro-2-(2-chloro-benzyloxy)-phenoxy]-azetidine trifluroacetate

MS (ESI): mass calcd. for C₁₆H₁₅Cl₂NO₂, 323.1; m/z found, 324.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.46 (dd, J=5.5, 3.8 Hz, 1H), 7.43-7.39 (m, 1H), 7.32-7.27 (m, 2H), 6.98 (dd, J=8.7, 2.4 Hz, 1H), 6.87 (d, J=8.7 Hz, 1H), 6.75 (d, J=2.4 Hz, 1H), 5.14 (s, 2H), 5.07-4.99 (m, 1H), 4.34-4.19 (m, 4H).

Example 36: 3-[5-Chloro-2-(4-chloro-benzyloxy)-phenoxy]-azetidine trifluoroacetate

MS (ESI): mass calcd. for C₁₆H₁₅Cl₂NO₂, 323.1; m/z found, 324.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.35 (q, J=8.6 Hz, 4H), 6.95 (dd, J=8.7, 2.4 Hz, 1H), 6.83 (d, J=8.7 Hz, 1H), 6.72 (d, J=2.4 Hz, 1H), 5.08-4.95 (m, 3H), 4.31-4.24 (m, 4H).

Example 37: 3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₆H₁₅Cl₂NO₂, 323.1; m/z found, 324.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.45 (s, 1H), 7.32-7.27 (m, 3H), 6.85 (td, J=8.5, 1.9 Hz, 1H), 6.81 (dd, J=8.6, 4.6 Hz, 1H), 6.59 (d, J=2.3 Hz, 1H), 5.06 (d, J=3.9 Hz, 2H), 5.00-4.95 (m, 1H), 3.95-3.84 (m, 4H).

Example 38: 3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-azetidine

Synthesized from the title compound of Example 37 according to general procedure 5. MS (ESI): mass calcd. for C₁₇H₁₇Cl₂NO₂, 337.1; m/z found, 338.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.45 (s, 1H), 7.32-7.27 (m, 3H), 6.84 (dd, J=8.6, 2.3 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 6.63 (d, J=2.3 Hz, 1H), 5.06 (s, 2H), 4.74-4.69 (m, 1H), 3.88-3.82 (m, 2H), 3.21-3.11 (m, 2H), 2.42 (s, 3H).

Example 39: 3-[5-Chloro-2-(3-trifluoromethyl-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₅ClF₃NO₂, 357.1; m/z found, 358.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.74 (s, 1H), 7.59 (t, J=8.6 Hz, 2H), 7.50 (t, J=7.7 Hz, 1H), 6.87 (dd, J=8.6, 2.2 Hz, 1H), 6.83 (d, J=8.6 Hz, 1H), 6.60 (d, J=1.7 Hz, 1H), 5.13 (s, 2H), 5.01-4.96 (m, 1H), 3.96-3.85 (m, 4H).

Example 40: 3-(2-Benzyloxy-5-chloro-phenoxy)-azetidine

MS (ESI): mass calcd. for C₁₆H₁₆ClNO₂, 289.1; m/z found, 290.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.39 (d, J=4.4 Hz, 4H), 7.36-7.31 (m, 1H), 6.96 (dd, J=8.7, 2.4 Hz, 1H), 6.86 (d, J=8.7 Hz, 1H), 6.74 (d, J=2.4 Hz, 1H), 5.03 (s, 2H), 5.01-4.95 (m, 1H), 4.39-4.15 (m, 4H).

Example 41: 3-[5-Chloro-2-(3-chloro-4-trifluoromethoxy-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₄Cl₂F₃NO₃, 407.0; m/z found, 408.0 [M+H]⁺. ¹H NMR (CD₃OD/CDC₃): 7.61-7.59 (m, 1H), 7.38-7.30 (m, 2H), 6.87 (dd, J=8.6, 2.3 Hz, 1H), 6.82 (d, J=8.6 Hz, 1H), 6.59 (d, J=2.3 Hz, 1H), 5.06 (s, 2H), 5.03-4.93 (m, 1H), 4.25-3.60 (m, 4H).

Example 42: 3-[5-Chloro-2-(4-trifluoromethoxy-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₅ClF₃NO₃, 373.1; m/z found, 374.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.46 (d, J=8.7 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 6.86 (dd, J=8.6, 2.6 Hz, 1H), 6.82 (d, J=8.6 Hz, 1H), 6.59 (d, J=2.2 Hz, 1H), 5.09 (s, 2H), 5.02-4.94 (m, 1H), 4.00-3.80 (m, 4H).

Example 43: 3-[5-Chloro-2-(4-trifluoromethyl-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₅ClF₃NO₂, 357.1; m/z found, 358.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.64 (d, J=8.1 Hz, 2H), 7.55 (d, J=8.1 Hz, 2H), 6.85 (dd, J=8.6, 2.3 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 6.60 (d, J=2.3 Hz, 1H), 5.15 (s, 2H), 5.02-4.94 (m, 1H), 4.01-3.79 (m, 4H).

Example 44: 4-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-benzonitrile

MS (ESI): mass calcd. for C₁₇H₁₅ClN₂O₂, 314.1; m/z found, 315.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.68 (d, J=8.3 Hz, 2H), 7.55 (d, J=8.0 Hz, 2H), 6.86 (dd, J=8.6, 2.4 Hz, 1H), 6.78 (d, J=8.6 Hz, 1H), 6.60 (d, J=2.3 Hz, 1H), 5.15, (s, 2H), 5.04-4.94 (m, 1H), 4.02-3.79 (m, 4H).

Example 45: 3-[2-(2,4-Bis-trifluoromethyl-benzyloxy)-5-chloro-phenoxy]-azetidine

¹H NMR (CDCl₃, CD₃OD): 8.04-7.92 (m, 2H), 7.01 (dd, J=8.7, 2.3 Hz, 1H), 6.94 (d, J=8.7 Hz, 1H), 6.84 (d, J=2.3 Hz, 1H), 5.36, (s, 2H), 5.20-2.11 (m, 1H), 4.49 (dd, J=12.4, 6.7 Hz, 2H), 4.22 (dd, J=12.4, 5.2 Hz, 2H).

Example 46: 3-[5-Chloro-2-(4-trifluoromethylsulfanyl-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₅ClF₃NO₂S, 389.1; m/z found, 390.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.67 (d, J=8.2 Hz, 2H), 7.49 (d, J=8.4 Hz, 2H), 6.86 (dd, J=8.6, 2.3 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 6.60 (d, J=2.3 Hz, 1H), 5.13 (s, 2H), 5.05-4.93 (m, 1H), 4.04-3.78 (m, 4H).

Example 47: 3-[5-Chloro-2-(4-fluoro-3-trifluoromethyl-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₄ClF₄NO₂, 375.1; m/z found, 377.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.77-7.70 (m, 1H), 7.64-7.57 (m, 1H), 7.25-7.18 (m, 1H), 6.88 (dd, J=8.6, 2.3 Hz, 1H), 6.83 (d, J=8.6 Hz, 1H), 6.59 (d, J=8.3 Hz, 1H), 5.08 (s, 2H), 5.02-4.94 (m, 1H), 3.98-3.90 (m, 2H), 3.87-3.80 (m, 2H).

Example 48: 3-[5-Chloro-2-(2-fluoro-4-trifluoromethyl-benzyloxy)-phenoxy]-azetidine

¹H NMR (CDCl₃): 7.70 (dd, J=7.6, 7.4 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.35 (d, J=9.8 Hz, 1H), 6.88-6.84 (m, 2H), 6.61 (d, J=2.0 Hz, 1H), 5.20 (s, 2H), 5.02-4.94 (m, 1H), 3.97-3.90 (m, 2H), 3.88-3.81 (m, 2H).

Example 49: 3-[5-Chloro-2-(4-chloro-3-trifluoromethyl-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₄C₁₂F₃NO₂, 391.0; m/z found, 392.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.73 (d, J=6.3 Hz, 1H), 7.63-7.58 (m, 1H), 7.21 (dd, J=9.4, 9.2 Hz, 1H), 6.90-6.81 (m, 2H), 6.59 (d, J=1.6 Hz, 1H), 5.10-5.05 (m, 1H), 5.08, (s, 2H), 5.05-4.95 (m, 4H).

Example 50: 3-[5-Chloro-2-(3,4-dichloro-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₆H₁₄C₁₃NO₂, 357.0; m/z found, 359.9 [M+H]⁺. ¹H NMR (CDCl₃): 7.56 (d, J=1.8 Hz, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.24 (dd, J=8.3, 1.9 Hz, 1H), 6.85 (dd, J=8.6, 2.3 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 6.58 (d, J=2.3 Hz, 1H), 5.04, (s, 2H), 5.05-5.00 (m, 1H), 4.52-3.00 (m, 4H).

Example 51: 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-pyridine

MS (ESI): mass calcd. for C₁₅H₁₅ClN₂O₂, 290.1; m/z found, 291.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.62-8.57 (m, 1H), 7.75-7.69 (m, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.25-7.20 (m, 1H), 6.85-6.82 (m, 2H), 6.60 (d, J=1.6 Hz, 1H), 5.24 (s, 2H), 5.09-4.94 (m, 1H), 4.18-3.64 (m, 4H).

Example 52: 3-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-pyridine

MS (ESI): mass calcd. for C₁₅H₁₅ClN₂O₂, 290.1; m/z found, 291.1 [M+H]⁺. ¹H NMR (CD₃OD/CDC₃): 8.68-8.61 (m, 1H), 8.53 (d, J=4.3 Hz, 1H), 7.86 (d, J=7.9 Hz, 1H), 7.45-7.37 (m, 1H), 6.93-6.87 (m, 2H), 6.63-6.60 (m, 1H), 5.13 (s, 2H), 5.04-4.94 (m, 1H), 4.12-3.70 (m, 4H).

Example 53: 4-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-pyridine

MS (ESI): mass calcd. for C₁₅H₁₅ClN₂O₂, 290.1; m/z found, 291.1 [M+H]⁺. ¹H NMR (CD₃OD/CDC₃): 8.56-8.53 (m, 2H), 7.50-7.44 (m, 2H), 6.92-6.86 (m, 2H), 6.66 (d, J=2.1 Hz, 1H), 5.18 (s, 2H), 5.09-5.01 (m, 1H), 4.04-3.94 (m, 2H), 3.88-3.80 (m, 2H).

Example 54: 3-[5-Chloro-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₅H₁₃ClF₃NO₃, 347.1; m/z found, 348.2 [M+H]⁺. ¹H NMR (CDCl₃): 6.90-6.88 (m, 2H), 6.77-6.76 (m, 1H), 6.60 (s, 1H), 6.46-6.45 (m, 1H), 5.05 (s, 2H), 4.98-4.93 (m, 1H), 3.94-3.90 (m, 2H), 3.85-3.82 (m, 2H).

Example 55: 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-furan-2-carboxylic acid ethyl ester

MS (ESI): mass calcd. for C₁₇H₁₈ClNO₅, 351.1; m/z found, 352.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.13 (d, J=3.4 Hz, 1H), 6.89-6.85 (m, 2H), 6.58 (d, J=1.6 Hz, 1H), 6.50 (d, J=3.4 Hz, 1H), 5.08 (s, 2H), 4.98-4.93 (m, 1H), 4.37 (q, J=7.1 Hz, 1H), 3.94-3.90 (m, 2H), 3.86-3.83 (m, 2H), 1.38 (t, J=7.1 Hz, 1H).

Example 56: 3-[5-Chloro-2-(4-chloro-2-methanesulfonyl-benzyloxy)-phenoxy]-azetidine

¹H NMR (CD₃OD/CDCl₃): 7.65 (s, 1H), 7.33-7.27 (m, 2H), 6.64 (d, J=8.7 Hz, 1H), 6.58 (dd, J=8.7, 2.3 Hz, 1H), 6.37 (d, J=2.3 Hz, 1H), 5.03 (s, 2H), 4.71-4.63 (m, 1H), 3.99 (dd, J=12.6, 6.6 Hz, 2H), 3.70 (dd, J=12.5, 5.1 Hz, 2H), 2.84 (s, 3H).

Example 57: 3-[5-Chloro-2-(2,4-difluoro-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₆H₁₄ClF₂NO₂, 325.1; m/z found, 327.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.52-7.43 (m, 1H), 6.92-6.80 (m, 4H), 6.60-6.58 (m, 1H), 5.10 (s, 2H), 5.00-4.93 (m, 1H), 4.11-3.69 (m, 4H).

Example 58: (R)-3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine

MS (ESI): mass calcd. for C₁₇H₁₇C₁₂NO₂, 337.1; m/z found, 338.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.43 (s, 1H), 7.30-7.25 (m, 3H), 6.87-6.81 (m, 3H), 5.02 (s, 2H), 4.83-4.81 (m, 1H), 3.23-3.17 (m, 2H), 2.99 (dd, J=12.8, 4.7 Hz, 1H), 2.91 (ddd, J=11.3, 8.5, 5.5 Hz, 1H), 2.11-2.00 (m, 2H).

Example 59: (R)-3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine

Synthesized from the title compound of Example 58 according to general procedure 5. MS (ESI): mass calcd. for C₁₈H₁₉Cl₂NO₂, 351.1; m/z found, 352.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.45 (s, 1H), 7.29-7.28 (m, 3H), 6.85-6.79 (m, 3H), 5.04 (s, 2H), 4.83-4.80 (m, 1H), 2.96 (dd, J=10.6, 6.1 Hz, 1H), 2.80-2.75 (m, 2H), 2.58-2.54 (m, 1H), 2.41 (s, 3H), 2.32-2.36 (m, 1H), 2.08-2.02 (m, 1H).

Example 60: (R)-3-[5-Chloro-2-(2-chloro-benzyloxy)-phenoxy]-pyrrolidine

MS (ESI): mass calcd. for C₁₇H₁₇C₁₂NO₂, 337.1; m/z found, 338.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.56-7.54 (m, 1H), 7.39-7.37 (m, 1H), 7.30-7.24 (m, 2H), 6.88-6.86 (m, 3H) 5.15 (s, 2H), 4.84-4.82 (m, 1H), 3.23-3.16 (m, 2H), 2.98 (dd, J=12.8, 4.6 Hz, 1H), 2.90 (ddd, J=11.3, 8.5, 5.5 Hz, 1H), 2.12-2.00 (m, 2H).

Example 61: (R)-3-[5-Chloro-2-(2-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine

Synthesized from the title compound of Example 60 according to general procedure 5. MS (ESI): mass calcd. for C₁₈H₁₉C₁₂NO₂, 351.1; m/z found, 352.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.60-7.58 (m, 1H), 7.38-7.37 (m, 1H), 7.29-7.23 (m, 2H), 6.85-6.82 (m, 3H) 5.17 (s, 2H), 4.85-4.81 (m, 1H), 2.95 (dd, J=10.6, 6.1 Hz, 1H), 2.78-2.73 (m, 2H), 2.57-2.53 (m, 1H), 2.39 (s, 3H), 2.32-2.36 (m, 1H), 2.08-2.02 (m, 1H).

Example 62: 4-(2-Benzyloxy-5-chloro-phenoxy)-piperidine

MS (ESI): mass calcd. for C₁₈H₂₀ClNO₂, 317.1; m/z found, 318.3 [M+H]⁺. ¹H NMR (CDCl₃): 7.42-7.40 (m, 2H), 7.38-7.34 (m, 2H), 7.32-7.29 (m, 1H), 6.93-6.93 (m, 1H), 6.87-6.82 (m, 2H), 5.08 (s, 2H), 4.35-4.29 (m, 1H), 3.17-3.11 (m, 2H), 2.68 (ddd, J=12.6, 9.3, 3.1 Hz, 2H), 2.02-1.96 (m, 2H), 1.74-1.66 (m, 2H).

Example 63: 4-[5-Chloro-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-piperidine hydrochloride

MS (ESI): mass calcd. for C₁₇H₁₇ClF₃NO₃, 375.1; m/z found, 378.2. ¹H NMR (DMSO-D₆): 9.10-9.00 (m, 2H), 7.24-7.23 (m, 2H), 7.15 (d, J=8.7 Hz, 1H), 7.01 (d, J=8.7, 2.5 Hz, 1H), 6.80 (d, J=3.2 Hz, 1H), 5.17 (s, 2H), 4.59-4.55 (m, 1H), 3.20-3.17 (m, 2H), 3.03-3.00 (m, 2H), 2.07-2.02 (m, 2H), 1.86-1.82 (m, 2H).

Example 64: 4-[5-Bromo-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-piperidine

MS (ESI): mass calcd. for C₁₇H₁₇BrF₃NO₃, 419.0; m/z found, 420.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.09 (d, J=2.3 Hz, 1H), 7.04 (dd, J=8.5, 2.3 Hz, 1H), 6.84 (d, J=8.6 Hz, 1H), 6.79-6.75 (m, 1H), 6.45 (d, J=3.3 Hz, 1H), 5.06 (s, 2H), 4.37-4.29 (m, 1H), 3.21-3.10 (m, 2H), 2.78-2.66 (m, 2H), 2.06-1.95 (m, 2H), 1.76-1.66 (m, 2H).

Example 65: 4-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-piperidine

MS (ESI): mass calcd. for C₁₈H₁₉BrClNO₂, 395.0; m/z found, 396.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.45 (s, 1H), 7.29-7.27 (m, 3H), 7.07 (d, J=7.1 Hz, 1H), 7.01 (dd, J=8.6, 2.3 Hz, 1H), 6.78 (d, J=8.6 Hz, 1H), 5.04 (s, 2H), 4.36-4.30 (m, 1H), 3.18-3.12 (m, 2H), 2.73-2.67 (m, 2H), 2.02-1.97 (m, 2H), 1.75-1.67 (m, 2H).

Example 66: 4-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-piperidine

Synthesized from the title compound of Example 65 according to general procedure 5. MS (ESI): mass calcd. for C₁₉H₂₁BrClNO₂, 409.0; m/z found, 410.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.46 (s, 1H), 7.30-7.28 (m, 3H), 7.06 (d, J=2.3 Hz, 1H), 7.01 (dd, J=8.6, 2.3 Hz, 1H), 6.79 (d, J=8.6 Hz, 1H), 5.04 (s, 2H), 4.32-4.29 (m, 1), 2.73-2.67 (m, 2H), 2.35-2.27 (m, 4H), 2.02-1.85 (m, 4H).

Example 67: 4-[5-Bromo-2-(2-fluoro-benzyloxy)-phenoxy]-piperidine

MS (ESI): mass calcd. for C₁₈H₁₉BrFNO₂, 379.1; m/z found, 380.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.52-7.49 (m, 1H), 7.33-7.28 (m, 1H), 7.15 (t, J=7.5 Hz, 1H), 7.09-7.05 (m, 2H), 7.03-7.01 (m, 1H), 6.83 (dd, J=8.6, 2.4 Hz, 1H), 5.12 (s, 2H), 4.34-4.29 (m, 1H), 3.15-3.13 (m, 2H), 2.71-2.62 (m, 2H), 2.00-1.94 (m, 2H), 1.72-1.66 (m, 2H).

Example 68: 4-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-piperidine

MS (ESI): mass calcd. for C₁₈H₁₉BrFNO₂, 379.1; m/z found, 380.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.35-7.31 (m, 1H), 7.18-7.15 (m, 2H), 7.07 (d, J=2.3 Hz, 1H), 7.02-6.98 (m, 2H), 6.78 (d, J=8.6 Hz, 1H), 5.07 (s, 2H), 4.36-4.31 (m, 1H), 3.17-3.14 (m, 2H), 2.71 (t, J=9.6 Hz, 2H), 2.03-2.00 (m, 2H), 1.75-1.67 (m, 2H).

Example 69: (±)-3-[5-Chloro-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-piperidine

MS (ESI): mass calcd. for C₁₇H₁₇ClF₃NO₃, 375.1; m/z found, 376.0 [M+H]⁺. ¹H NMR (CDCl₃): 6.96-6.95 (m, 1H), 6.88-6.87 (m, 2H), 6.76-6.75 (m, 1H), 6.45-6.44 (m, 1H), 5.04 (s, 2H), 4.22-4.17 (m, 1H), 3.12 (dd, J=2.2, 12.7 Hz, 1H), 2.88-2.82 (m, 2H), 2.78-2.72 (m, 1H), 2.02-1.96 (m, 1H), 1.85-1.74 (m, 2H), 1.53-1.45 (m, 1H).

Example 70: (±)-3-(2-Benzyloxy-5-chloro-phenoxy)-piperidine

MS (ESI): mass calcd. for C₁₈H₂₀ClNO₂, 317.12; m/z found, 318.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.45-7.28 (m, 5H), 6.95 (d, J=2.1 Hz, 1H), 6.90-6.81 (m, 2H), 5.08 (s, 2H), 4.20 (dq, J=10.2, 3.3 Hz, 1H), 3.11 (dd, J=12.7, 2.3 Hz, 1H), 2.91-2.78 (m, 2H), 2.78-2.69 (m, 1H), 2.05-1.94 (m, 1H), 1.88-1.74 (m, 2H), 1.53-1.41 (m, 1H).

Example 71: (±)-3-[5-Chloro-2-(3-trifluoromethyl-benzyloxy)-phenoxy]-piperidine

MS (ESI): mass calcd. for C₁₉H₁₉ClF₃NO₂, 385.11; m/z found, 386.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.75 (s, 1H), 7.62-7.56 (m, 2H), 7.50 (t, J=7.7 Hz, 1H), 6.96 (d, J=2.3 Hz, 1H), 6.89 (dd, J=8.6, 2.3 Hz, 1H), 6.84 (d, J=8.6 Hz, 1H), 5.12 (s, 2H), 4.28-4.16 (m, 1H), 3.13 (dd, J=12.6, 2.3 Hz, 1H), 2.91-2.80 (m, 2H), 2.78-2.67 (m, 1H), 2.08-1.94 (m, 1H), 1.88-1.73 (m, 2H), 1.55-1.40 (m, 1H).

Example 72: 3-(5-Chloro-2-cyclopentyloxy-phenoxy)-azetidine trifluoroacetate

MS (ESI): mass calcd. for C₁₄H₁₈ClNO₂, 267.1; m/z found, 268.2 [M+H]⁺. ¹H NMR (CDCl₃): 6.97 (dd, J=8.7, 2.5 Hz, 1H), 6.81 (d, J=8.8 Hz, 1H), 6.75 (d, J=2.5 Hz, 1H), 5.04-4.99 (m, 1H), 4.76-4.67 (m, 1H), 4.38-4.27 (m, 4H), 1.96-1.87 (m, 2H), 1.84-1.74 (m, 4H), 1.69-1.59 (m, 2H).

Example 73: 3-(5-Chloro-2-cyclohexylmethoxy-phenoxy)-azetidine trifluoroacetate

MS (ESI): mass calcd. for C₁₆H₂₂ClNO₂, 295.1; m/z found, 296.2 [M+H]⁺. ¹H NMR (CDCl₃): 6.97 (dd, J=8.7, 2.3 Hz, 1H), 6.80 (d, J=8.7 Hz, 1H), 6.74 (d, J=2.4 Hz, 1H), 5.15-4.97 (m, 1H), 4.44-4.36 (m, 2H), 4.30 (s, 2H), 3.74 (d, J=6.3 Hz, 2H), 1.89-1.65 (m, 6H), 1.36-1.14 (m, 3H), 1.03 (m, 2H).

Example 74: 3-(5-Bromo-2-cyclohexylmethoxy-phenoxy)-azetidine

MS (ESI): mass calcd. for C₁₆H₂₂BrNO₂, 339.1; m/z found, 340.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.01 (dd, J=8.6, 2.3 Hz, 1H), 6.74 (d, J=8.6 Hz, 1H), 6.71 (d, J=2.3 Hz, 1H), 4.97-4.92 (m, 1H), 3.92-3.83 (m, 4H), 3.75 (d, J=6.4 Hz, 2H), 1.95-1.63 (m, 6H), 1.36-1.14 (m, 3H), 1.10-0.93 (m, 2H).

Example 75: 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-trifluoromethyl-furan-3-carboxylic acid trifluoroacetate

Step A: Preparation of 5-Bromomethyl-2-trifluoromethyl-furan-3-carboxylic acid ethyl ester

To a solution of 5-methyl-2-trifluoromethyl-furan-3-carboxylic acid ethyl ester (0.95 g, 4.5 mmol) in CCl₄ (12 mL) was added N-bromosuccinimide (0.84 g, 4.8 mmol) followed by AIBN (0.004 g, 0.01 mmol). After refluxing for 2 h, analytical HPLC analysis confirmed the reaction was complete. The reaction was cooled to rt, then CH₂Cl₂ and sat'd NaHCO₃ (aq.) were added. The organic portion was separated and dried to provide the crude residue as a yellow oil. This material was purified by RP HPLC to provide the title compound (510 mg, 38%). MS (ESI): mass calcd. for C₉H₈BrF₃O₃, 300.0; m/z found, 302.9 [M+H]⁺. ¹H NMR (CDCl₃): 6.84 (s, 1H), 4.44 (s, 2H), 4.34 (q, J=7.2 Hz, 2H), 1.36 (t, J=7.1 Hz, 3H).

Step B: Preparation of 3-[2-(4-Carboxy-5-trifluoromethyl-furan-2-ylmethoxy)-5-chloro-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester

The title compound was prepared as described in Example 1 Step D using 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (0.15 g, 0.50 mmol), the title compound of Step A (0.18 g, 0.60 mmol), Cs₂CO₃ (0.41 g, 1.2 mmol), KI (0.12 g, 0.70 mmol) in DMF, except upon completion of the reaction 1N NaOH and EtOAc were added. The organic layer was washed with 1N NaOH and dried. The crude material was purified by RP HPLC to provide the title compound. ¹H NMR (CDCl₃): 7.20-6.92 (m, 1H), 6.91-6.80 (m, 2H), 6.77-6.69 (m, 1H), 6.53 (d, J=2.1 Hz, 1H), 4.87 (s, 2H), 4.79-4.69 (m, 1H), 4.27-4.12 (m, 2H), 4.00-3.88 (m, 2H), 1.38 (s, 9H).

Step C: Preparation of 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-trifluoromethyl-furan-3-carboxylic acid trifluoroacetate

Prepared from the title compound of Step B using general procedure 1. MS (ESI): mass calcd. for C₁₆H₁₃ClF₃NO₅ [M-TFA], 391.0; m/z found, 392.9 [M+H]⁺. ¹H NMR (CD₃OD): 7.10 (d, J=8.7 Hz, 1H), 7.03 (dd, J=8.7, 2.4 Hz, 1H), 6.99 (s, 1H), 6.88 (d, J=2.4 Hz, 1H), 5.14 (s, 2H), 5.11-5.04 (m, 1H), 4.49 (dd, J=12.4, 6.6 Hz, 2H), 4.22 (dd, J=12.4, 4.9 Hz, 2H).

Example 76: 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-trifluoromethyl-furan-3-carboxylic acid ethyl ester

Step A: Preparation of 3-[5-Chloro-2-(4-ethoxycarbonyl-5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester

The title compound was prepared as described in Example 1 Step D using 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (0.3 g, 1.0 mmol), the title compound of Example 75 Step A (0.75 g, 2.5 mmol), Cs₂CO₃ (0.80 g, 2.4 mmol) and KI (0.23 g, 1.4 mmol) in DMF (15 mL). The crude material was purified by RP HPLC to provide the title compound (0.37 g, 71%). ¹H NMR (CDCl₃): 7.20-6.92 (m, 1H), 6.91-6.80 (m, 2H), 6.77-6.69 (m, 1H), 6.53 (d, J=2.1 Hz, 1H), 4.87 (s, 2H), 4.79-4.69 (m, 1H), 4.27-4.12 (m, 2H), 4.00-3.88 (m, 2H), 1.38 (s, 9H).

Step B: Preparation of 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-trifluoromethyl-furan-3-carboxylic acid ethyl ester: Prepared from the title compound of Step A using general procedure 1. MS (ESI): mass calcd. for C₁₈H₁₇ClF₃NO₅, 419.1; m/z found, 420.0 [M+H]⁺. ¹H NMR (CDCl₃): 6.94-7.80 (m, 3H), 6.65-6.56 (m, 1H), 5.05 (s, 2H), 5.01-4.92 (m, 1H), 4.34 (q, J=7.2 Hz, 2H), 3.97-3.81 (m, 4H), 1.36 (t, J=7.1 Hz, 3H).

Example 77: 5-[4-Chloro-2-(1-methyl-azetidin-3-yloxy)-phenoxymethyl]-2-trifluoromethyl-furan-3-yl]-methanol

Step A: Preparation of 5-[4-Chloro-2-(1-methyl-azetidin-3-yloxy)-phenoxymethyl]-2-trifluoromethyl-furan-3-yl]-methanol

To a solution of the title compound of Example 76 Step A (0.05 g, 0.1 mmol) at −78° C. was added DIBAL-H (1.0M in THF, 0.24 mL). After addition was complete, the bath was replaced with a 0° C. bath and allowed to stir for 1 h. Then, an additional aliquot of DIBAL-H (1.0M in THF, 1 mL) was added. After 3 h, the reaction was quenched with a saturated solution of sodium potassium tartrate (aq.) and allowed to stir overnight. The mixture was extracted with EtOAc (2×) and the combined organic layers were dried. The product was purified by RP HPLC to provide the title compound (0.004 g, 10%). MS (ESI): mass calcd. for C₁₇H₁₇ClF₃NO₄, 391.1; m/z found, 392.1 [M+H]⁺. ¹H NMR (CDCl₃): 6.94 (d, J=8.6 Hz, 1H), 6.89 (dd, J=8.6, 2.3 Hz, 1H), 6.65 (s, 1H), 6.54 (d, J=2.3 Hz, 1H), 5.02 (s, 2H), 4.73-4.66 (m, 1H), 4.64 (d, J=1.4 Hz, 2H), 3.76-3.69 (m, 2H), 3.27-3.21 (m, 2H), 2.41 (s, 3H).

Example 78: 3-[5-Chloro-2-(5-methyl-2-trifluoromethyl-furan-3-ylmethoxy)-phenoxy]-azetidine

Step A: Preparation of (5-Methyl-2-trifluoromethyl-furan-3-yl)-methanol

To a solution of 5-methyl-2-trifluoromethyl-furan-3-carboxylic acid ethyl ester (0.83 g, 3.7 mmol) in Et₂O at 0° C., was added DIBAL-H (1.0M in THF, 1.5 mL). After 10 min, the ice bath was removed and additional DIBAL-H was added (1.0M in THF, 14.5 mL). After 2 h, the reaction was quenched with a saturated solution of sodium potassium tartrate (aq.) and allowed to stir overnight. After 18 h, EtOAc was added and the organic layer separated and dried provide the title compound (0.39 g, 58%). ¹H NMR (CDCl₃): 6.19 (s, 1H), 4.62 (s, 2H), 2.36-2.28 (m, 3H).

Step B: Preparation of 3-[5-chloro-2-(5-methyl-2-trifluoromethyl-furan-3-ylmethoxy)-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester

Synthesized from the title compound of Step A and 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester using general procedure 7. MS (ESI): mass calcd. for C₂₁H₂₃ClF₃NO₅, 461.1; m/z found, 485.9 [M+Na]⁺. ¹H NMR 6.91 (dd, J=8.6, 2.3 Hz, 1H), 6.84 (d, J=8.6 Hz, 1H), 6.55 (d, J=2.3 Hz, 1H), 6.22 (s, 1H), 5.07-5.00 (m, 2H), 4.90-4.81 (m, 1H), 4.30 (ddd, J=9.7, 6.5, 0.8 Hz, 2H), 4.06 (dd, J=9.8, 4.0 Hz, 2H), 2.34 (s, 3H), 1.45 (s, 9H).

Step C: Preparation of 3-[5-Chloro-2-(5-methyl-2-trifluoromethyl-furan-3-ylmethoxy)-phenoxy]-azetidine

Synthesized from the title compound of Step B using general procedure 1. MS (ESI): mass calcd. for C₁₆H₁₅ClF₃NO₃, 361.1; m/z found, 362.1 [M+H]⁺. ¹H NMR (CDCl₃): 6.86 (dd, J=8.6, 2.2 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 6.58 (d, J=2.2 Hz, 1H), 6.23 (s, 1H), 5.03 (s, 2H), 5.01-4.93 (m, 1H), 4.01-3.77 (m, 4H), 2.33 (s, 3H).

Example 79: 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-6-trifluoromethyl-pyridine

Step A: Preparation of (6-Trifluoromethyl-pyridin-2-yl)-methanol

To a solution of 6-trifluoromethyl-pyridine-2-carboxylic acid (500 mg, 3 mmol) in dry THF at 0° C., was added triethylamine (0.36 mL, 2.6 mmol) followed by ethyl chloroformate (0.25 mL, 2.6 mmol). After 30 min, LiBH₄ (2M in THF, 3.3 mL, 6.5 mmol) was added. After an additional 30 min, the ice bath was removed. After 1 h, the reaction was cooled to 0° C. and quenched with MeOH followed by 1N NaOH and EtOAc. The pH of the solution was adjusted to pH=5 with 1N HCl and the mixture extracted with EtOAc (2×). The combined organic fractions were dried to provide the title compound that was used without further purification. ¹H NMR (CDCl₃): 7.89 (dd, J=7.8, 7.8 Hz, 1H), 7.61 (d, J=7.7 Hz, 1H), 7.51 (d, J=7.9 Hz, 1H), 4.85 (s, 2H).

Step B: Preparation of 3-[5-Chloro-2-(6-trifluoromethyl-pyridin-2-ylmethoxy)-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester

Prepared from the title compound of Step A and 3-(5-Chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester using general procedure 7.

Step C: Preparation of 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-6-trifluoromethyl-pyridine

Prepared from the title compound of Step B according to general procedure 1. MS (ESI): mass calcd. for C₁₆H₁₄ClF₃N₂O₂, 358.1; m/z found, 359.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.92 (dd, J=7.8, 7.8 Hz, 1H), 7.81 (d, J=7.9 Hz, 1H), 7.63 (d, J=7.7 Hz, 1H), 6.87 (dd, J=8.6, 2.1 Hz, 1H), 6.61 (d, J=2.1, 1H), 5.29 (s, 2H), 5.21-4.99 (m, 1H), 4.21-1.15 (br m, 4H).

Examples 80-89 were prepared using the appropriate alcohol and phenol according to general procedure 7.

Example 80: 3-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-methyl-6-trifluoromethyl-pyridine

MS (ESI): mass calcd. for C₁₇H₁₆ClF₃N₂O₂, 372.1; m/z found, 373.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.93 (d, J=7.9 Hz, 1H), 7.55 (d, J=7.9 Hz, 1H), 6.89 (dd, J=8.6, 2.2 Hz, 1H), 6.85 (d, J=8.6 Hz, 1H), 6.60 (d, J=2.2 Hz, 1H), 5.11 (s, 2H), 5.03-4.92 (m, 1H), 4.08-3.69 (m, 4H), 2.66 (s, 3H).

Example 81: 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-4-trifluoromethyl-pyridine

MS (ESI): mass calcd. for C₁₆H₁₄ClF₃N₂O₂, 358.1; m/z found, 358.9 [M+H]⁺. ¹H NMR (CDCl₃): 8.86 (s, 1H), 7.98 (d, J=7.9 Hz, 1H), 7.73 (d, J=8.2 Hz, 1H), 6.87 (dd, J=8.6, 2.1 Hz, 1H), 6.82 (d, J=8.6 Hz, 1H), 6.61 (d, J=1.9 Hz, 1H), 5.28 (s, 2H), 5.08-4.98 (m, 1H), 4.08-3.97 (m, 2H), 3.96-3.85 (m, 2H).

Example 82: 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-2-trifluoromethyl-pyridine

MS (ESI): mass calcd. for C₁₆H₁₄ClF₃N₂O₂, 358.1; m/z found, 359.0 [M+H]⁺. ¹H NMR (CDCl₃): 8.81 (s, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.72 (d, J=8.1 Hz, 1H), 6.90 (dd, J=8.6, 2.2 Hz, 1H), 6.86 (d, J=8.6 Hz, 1H), 6.60 (d, J=2.2 Hz, 1H), 5.18 (s, 2H), 5.03-4.95 (m, 1H), 4.02-3.95 (m, 2H), 3.89-3.82 (m, 2H).

Example 83: 3-[2-(Benzofuran-5-ylmethoxy)-5-chloro-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₆ClNO₃, 329.1; m/z found, 330.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.65-7.64 (m, 2H) 7.50 (d, J=8.5 Hz, 1H), 7.35 (dd, J=8.5, 1.6 Hz, 1H), 6.87-6.82 (m, 2H), 6.76 (d, J=1.3 Hz, 1H), 6.59 (s, 1H), 5.18 (s, 2H), 5.02-4.92 (m, 1H), 4.06-3.79 (m, 4H).

Example 84: 6-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-benzothiazole

MS (ESI): mass calcd. for C₁₇H₁₅ClN₂O₂S, 346.1; m/z found, 347.0 [M+H]⁺. ¹H NMR (CDCl₃): 9.01 (s, 1H), 8.14 (d, J=8.4 Hz, 1H), 8.05 (s, 1H), 7.57 (dd, J=8.4, 1.6 Hz, 1H), 6.85 (d, J=1.2 Hz, 2H), 6.60 (s, 1H), 5.35 (s, 2H), 5.00-4.98 (m, 1H), 3.93-3.87 (m, 4H).

Example 85: 6-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-1-methyl-1H-benzotriazole

MS (ESI): mass calcd. for C₁₇H₁₇ClN₄O₂, 344.1; m/z found, 345.0 [M+H]⁺. ¹H NMR (CDCl₃): 8.10 (s, 1H), 7.61 (dd, J=8.6, 1.3 Hz, 1H), 7.53 (d, J=8.6 Hz, 1H), 6.88-6.80 (m, 2H), 6.59 (d, J=1.9 Hz, 1H), 5.26 (s, 2H), 5.02-4.96 (m, 1H), 4.31 (s, 3H), 3.97-3.82 (m, 4H).

Example 86: 3-[5-Chloro-2-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₄ClF₂NO₄, 369.1; m/z found, 370.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.20 (d, J=1.2 Hz, 1H), 7.11 (dd, J=8.2, 1.5 Hz, 1H), 7.04 (d, J=8.2 Hz, 1H), 6.86 (dd, J=8.6, 2.3 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 6.59 (d, J=2.3 Hz, 1H), 5.06 (s, 2H), 5.01-4.95 (m, 1H), 3.96-3.83 (m, 4H).

Example 87: 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-oxazole

MS (ESI): mass calcd. for C₁₃H₁₃ClN₂O₃, 280.1; m/z found, 281.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.91 (s, 1H), 7.13 (s, 1H), 6.90-6.87 (m, 2H), 6.59 (d, J=1.9 Hz, 1H), 5.10 (s, 2H), 5.00-4.91 (m, 1H), 3.97-3.89 (m, 2H), 3.87-3.79 (m, 2H).

Example 88: 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-thiazole

MS (ESI): mass calcd. for C₁₃H₁₃ClN₂O₂S, 296.0; m/z found, 297.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.80 (t, J=3.1 Hz, 1H), 7.38 (t, J=3.3 Hz, 1H), 6.96-6.84 (m, 2H), 6.63 (dd, J=11.1, 2.3 Hz, 1H), 5.41-5.37 (m, 2H), 5.04-4.78 (m, 1H), 4.01-3.93 (m, 1H), 3.92-3.83 (m, 2H), 3.31-3.23 (m, 1H)

Example 89: 3-[2-(Benzofuran-2-ylmethoxy)-5-chloro-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₆ClNO₃, 329.1; m/z found, 330.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.56 (d, J=7.7 Hz, 1H), 7.50 (dd, J=8.2, 0.7 Hz, 1H), 7.34-7.28 (m, 1H), 7.23 (dt, J=7.5, 1.0 Hz, 1H), 6.96 (d, J=8.6 Hz, 1H), 6.87 (dd, J=8.6, 2.4 Hz, 1H), 6.73 (d, J=0.5 Hz, 1H), 6.57 (d, J=2.4 Hz, 1H), 5.17 (s, 2H), 4.95-4.89 (m, 1H), 3.93-3.69 (m, 4H).

Example 90: (R)-3-(2-Benzyloxy-4-chloro-phenoxy)-pyrrolidine

Step A: Preparation of 3-(4-chloro-2-formyl-phenoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester

To (S)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (2.0 g, 10.9 mmol) in CH₂Cl₂ (50 mL) at 0° C. was added Et₃N (1.4 g, 1.9 mL, 13.4 mmol) and methanesulfonyl chloride (1.38 g, 0.94 mL, 12.1 mmol). After 1 h, brine was added and the mixture extracted with CH₂Cl₂ (2×). The combined organics were dried to give 3-methanesulfonyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester that was used without further purification.

To this compound in DMF (50 mL) was added 5-chloro-2-hydroxy-benzaldehyde (1.9 g, 12.1 mmol) and K₂CO₃ (1.8 g, 13.1 mmol). The reaction was heated at 90° C. for 2 h, then cooled to rt and H₂O was added. The mixture was extracted with EtOAc (2×). The combined organics were washed with brine and dried. Silica gel chromatography (10-50% EtOAc in hexanes) gave 1.85 g (52%) of the title compound. ¹H NMR (CDCl₃): 10.36 (s, 1H), 7.81 (s, 1H), 7.50 (s, 1H), 6.90 (d, J=8.9 Hz, 1H), 5.00 (s, 1H), 3.72-3.50 (m, 4H), 2.26-2.18 (m, 2H), 1.47 (s, 9H).

Step B: Preparation of 3-(4-chloro-2-hydroxy-phenoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester

To a CH₂Cl₂ (25 mL) solution of the title compound of Step A (1.4 g, 4.3 mmol) was added 77% m-CPBA (1.4 g, 6.2 mmol). After 18 h, additional CH₂Cl₂ was added and the reaction washed with saturated NaHCO₃ (aq.) and 10% Na₂S₂O₅ until KI paper negative. The combined organic layers were dried then treated with MeOH (25 mL) and 1N NaOH (25 mL). After 15 h, the reaction was acidified with 1M KHSO₄ then extracted with EtOAc (2×). The combined organic layers were washed with brine and dried to give the title compound as a white solid. ¹H NMR (CDCl₃): 6.96 (s, 1H), 6.82-6.80 (m, 1H), 6.73 (d, J=8.6 Hz, 1H), 5.62 (s, 1H), 4.91 (s, 1H), 3.66-3.46 (m, 4H), 2.20-2.11 (m, 2H), 1.47 (s, 9H).

Step C: Preparation of 3-(2-Benzyloxy-4-chloro-phenoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester

Prepared according to Example 1 Step D using the title compound of Step B. MS (ESI): mass calcd. for C₂₂H₂₆ClNO₄, 403.2; m/z found, 426.2 [M+Na]⁺, 348.2 [M−56]⁺. ¹H NMR (CDCl₃): 7.43-7.36 (m, 4H), 7.35-7.30 (m, 1H), 6.95 (d, J=2.4 Hz, 1H), 6.88 (dd, J=8.5, 2.4 Hz, 1H), 6.82 (d, J=8.5 Hz, 1H), 5.07 (s, 2H), 4.89-4.85 (m, 1H), 3.71-3.45 (m, 4H), 2.24-2.12 (m, 1H), 2.07-1.94 (m, 1H), 1.46 (s, 9H).

Step D: Preparation of (R)-3-(2-Benzyloxy-4-chloro-phenoxy)-pyrrolidine

Prepared according to general procedure 1 using the title compound of Step C. MS (ESI): mass calcd. for C₁₇H₁₈ClNO₂, 303.1; m/z found, 304.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.45-7.36 (m, 4H), 7.35-7.30 (m, 1H), 6.94 (d, J=2.4 Hz, 1H), 6.88 (dd, J=8.6, 2.4 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 5.06 (s, 2H), 4.86 (s, 1H), 3.25 (d, J=2.1 Hz, 2H), 2.25-1.73 (m, 4H).

Example 91: (R)-3-(2-Benzyloxy-4-chloro-phenoxy)-1-methyl-pyrrolidine

Synthesized from the title compound of Example 90 according to general procedure 5. MS (ESI): mass calcd. for C₁₈H₂₀ClNO₂, 317.1; m/z found, 318.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.44-7.32 (m, 5H), 6.91 (d, J=2.3 Hz, 1H), 6.86 (dd, J=8.5, 2.4 Hz, 1H), 6.75 (d, J=8.6 Hz, 1H), 5.08 (s, 2H), 4.81 (td, J=10.4, 5.1 Hz, 1H), 2.90 (dd, J=10.1, 6.1 Hz, 1H), 2.74 (d, J=8.9 Hz, 2H), 2.53 (dd, J=13.8, 7.9 Hz, 1H), 2.38 (s, 3H), 2.28-2.21 (m, 1H), 2.08-1.98 (m, 1H).

Example 92: (R)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine

Synthesized according to Example 90 using 3-chlorobenzyl bromide. MS (ESI): mass calcd. for C₁₇H₁₇Cl₂NO₂, 337.1; m/z found, 338.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.40 (s, 1H), 7.29-7.20 (m, 3H), 6.86 (dd, J=7.1, 2.2 Hz, 2H), 6.79-6.74 (m, 1H), 4.99 (s, 2H), 4.77 (t, J=5.1 Hz, 1H), 3.18-3.13 (m, 2H), 2.92-2.86 (m, 2H), 2.11-1.81 (m, 2H).

Example 93: (R)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine

Synthesized from the title compound of Example 92 according to general procedure 5. MS (ESI): mass calcd. for C₁₈H₁₉Cl₂NO₂, 351.1; m/z found, 352.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.47 (s, 1H), 7.30 (s, 3H), 6.88 (dd, J=7.3, 2.2 Hz, 2H), 6.77-6.74 (m, 1H), 5.04 (s, 2H), 4.85-4.73 (m, 1H), 2.96-2.86 (m, 1H), 2.79-2.68 (m, 2H), 2.56-2.50 (m, 1H), 2.39 (s, 3H), 2.31-2.17 (m, 1H), 2.05-1.95 (m, 1H).

Example 94: (S)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine

Synthesized according to Example 90 using (R)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester and 3-chlorobenzyl bromide. MS (ESI): mass calcd. for C₁₇H₁₇Cl₂NO₂, 337.1; m/z found, 338.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.44 (s, 1H), 7.36-7.24 (m, 3H), 6.94-6.86 (m, 2H), 6.84-6.78 (m, 1H), 5.08 (s, 2H), 4.81 (t, J=5.0 Hz, 1H), 3.26-3.08 (m, 2H), 3.00-2.84 (m, 2H), 2.12-1.91 (m, 2H).

Examples 95-100 were prepared using 1-methyl-pyrrolidin-3-ol and the appropriately substituted phenol (synthesized according to Example 90) according to general procedure 7 using resin bound PPh₃.

Example 95: (±)-3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine

MS (ESI): mass calcd. for C₁₈H₁₉BrClNO₂, 395.0; m/z found, 396.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.46 (s, 1H), 7.33-7.24 (m, 3H), 6.98 (dd, J=8.5, 2.3 Hz, 1H), 6.94 (d, J=2.3 Hz, 1H), 6.76 (d, J=8.5 Hz, 1H), 5.04 (s, 2H), 4.82 (m, 1H), 2.95 (dd, J=10.5, 6.1 Hz, 1H), 2.82-2.73 (m, 2H), 2.55 (m, 1H), 2.41 (s, 3H), 2.31 (m, 1H), 2.10-2.00 (m, 1H).

Example 96: (±)-3-[5-Bromo-2-(3-methoxy-benzyloxy)-phenoxy]-1-methyl-pyrrolidine

MS (ESI): mass calcd. for C₁₉H₂₂BrNO₃, 391.1; m/z found, 391.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.31-7.23 (m, 1H), 6.99-6.96 (m, 3H), 6.93 (d, J=2.3 Hz, 1H), 6.87-6.82 (m, 1H), 6.76 (d, J=8.5 Hz, 1H), 5.06 (s, 2H), 4.86-4.79 (m, 1H), 3.81 (s, 3H), 2.94 (dd, J=10.6, 6.1 Hz, 1H), 2.79-2.73 (m, 2H), 2.54 (m, 1H), 2.39 (s, 3H), 2.29 (m, 1H), 2.05 (m, 1H).

Example 97: (±)-3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine

MS (ESI): mass calcd. for C₁₈H₁₉BrFNO₂, 379.1; m/z found, 380.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-D₆): 7.32 (m, 1H), 7.17 (d, J=7.3 Hz, 2H), 7.02-6.96 (m, 2H), 6.94 (d, J=2.3 Hz, 1H), 6.75 (d, J=8.5 Hz, 1H), 5.07 (s, 2H), 4.82 (m, 1H), 2.94 (m, 1H), 2.82-2.73 (m, 2H), 2.55 (m, 1H), 2.40 (s, 3H), 2.31 (m, 1H), 2.07-2.02 (m, 1H).

Example 98: (±)-3-(2-Benzyloxy-5-bromo-phenoxy)-1-methyl-pyrrolidine

MS (ESI): mass calcd. for C₁₈H₂₀BrNO₂, 361.1; m/z found, 362.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.41 (m, 2H), 7.39-7.34 (m, 2H), 7.30 (m, 1H), 6.97 (dd, J=8.5, 2.3 Hz, 1H), 6.93 (d, J=2.3 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 5.08 (s, 2H), 4.86-4.76 (m, 1H), 2.93 (m, 1H), 2.80-2.72 (m, 2H), 2.57-2.50 (m, 1H), 2.39 (s, 3H), 2.29 (m, 1H), 2.09-1.99 (m, 1H).

Example 99: (±)-Methanesulfonic acid 3-[4-bromo-2-(1-methyl-pyrrolidin-3-yloxy)-phenoxymethyl]-phenyl ester

MS (ESI): mass calcd. for C₁₉H₂₂BrNO₅S, 455.1; m/z found, 456.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.46-7.35 (m, 3H), 7.23 (m, 1H), 6.98 (dd, J=8.5, 2.3 Hz, 1H), 6.93 (d, J=2.2 Hz, 1H), 6.75 (d, J=8.5 Hz, 1H), 5.08 (s, 2H), 4.81 (m, 1H), 3.13 (s, 3H), 2.89 (m, 1H), 2.82-2.74 (m, 2H), 2.55-2.46 (m, 1H), 2.39 (s, 3H), 2.31 (m, 1H), 2.03 (m, 1H).

Example 100: (±)-Methanesulfonic acid 3-[2-(1-methyl-pyrrolidin-3-yloxy)-phenoxymethyl]-phenyl ester

MS (ESI): mass calcd. for C₁₉H₂₃NO₅S, 377.1; m/z found, 378.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.42 (m, 3H), 7.26-7.20 (m, 1H), 6.98-6.80 (m, 4H), 5.13 (s, 2H), 4.86 (m, 1H), 3.12 (s, 3H), 2.93 (dd, J=10.5, 6.1 Hz, 1H), 2.81-2.71 (m, 2H), 2.60-2.49 (m, 1H), 2.40 (s, 3H), 2.30 (m, 1H), 2.11-2.00 (m, 1H).

Example 101: (S)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine

Step A: Preparation of (R)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester

To (S)-1-(3-trifluoromethyl-phenyl)-ethanol (2.30 g, 12.1 mmol), 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (3.80 g, 12.7 mmol) and PPh₃ (3.80 g, 14.5 mmol) in THF (60 mL) at 0° C. was added DEAD (2.3 g, 2.1 mL, 13 mmol) in THF (10 mL) dropwise over 30 min. After 48 h, the reaction was concentrated and 15% EtOAc in hexanes was added. The flask was cooled to 0° C. and filtered. The filtrate was concentrated and this procedure repeated 2 more times. The resulting oil was then purified using silica gel chromatography (10-40% EtOAc in hexanes) to give 5.17 g (91%) of the title compound as a clear oil. ¹H NMR (CDCl₃): 7.66 (s, 1H), 7.56-7.53 (m, 2H), 7.46 (t, J=7.7 Hz, 1H), 6.79 (dd, J=8.6, 2.4 Hz, 1H), 6.71 (d, J=8.6 Hz, 1H), 6.52 (d, J=2.4 Hz, 1H), 5.29 (q, J=6.5 Hz, 1H), 4.88-4.82 (m, 1H), 4.33-4.29 (m, 2H), 4.08-4.01 (m, 2H), 1.67 (d, J=6.5 Hz, 3H), 1.46 (s, 9H).

Step B: Preparation of (S)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine

To the title compound of Step A (5.1 g, 10.8 mmol) in CH₂Cl₂ (50 mL) at 0° C. was added TFA (50 mL). After 1 h, PhCH₃ (50 mL) was added and the mixture concentrated. The resulting oil was neutralized with saturated NaHCO₃ (aq.) and extracted with CH₂Cl₂ (2×). The combined organics were dried and concentrated. Silica gel chromatography (1-7% 2M NH₃/MeOH in CH₂Cl₂) gave 3.38 g (83% yield) of the title compound as a clear oil. MS (ESI): mass calcd. for C₁₈H₁₇ClF₃NO₂, 371.1; m/z found, 372.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.70 (s, 1H), 7.56-7.53 (m, 2H), 7.45 (t, J=7.7 Hz, 1H), 6.77 (dd, J=8.6, 2.3 Hz, 1H), 6.70 (d, J=8.6 Hz, 1H), 6.55 (d, J=2.4 Hz, 1H), 5.30 (q, J=6.3 Hz, 1H), 5.00-4.94 (m, 1H), 3.97-3.93 (m, 2H), 3.89-3.81 (m, 2H), 1.66 (d, J=6.5 Hz, 3H).

Unless otherwise specified the compounds in Examples 102-144 were prepared similar to Example 101 using the appropriately substituted phenols and alcohols.

Example 102: (S)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine trifluoroacetate

Prepared using (R)-1-(3-trifluoromethyl-phenyl)-ethanol. MS (ESI): mass calcd. for C₁₈H₁₇ClF₃NO₂, 371.1; m/z found, 372.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.61 (s, 1H), 7.55-7.45 (m, 3H), 6.86 (dd, J=8.7, 2.2 Hz, 1H), 6.68-6.66 (m, 2H), 5.30 (q, J=6.3 Hz, 1H), 5.11 (s, 1H), 4.44-4.32 (m, 4H), 1.66 (d, J=6.4 Hz, 3H).

Example 103: (S)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-1-methyl-azetidine

Prepared according to general procedure 5 using the title compound of Example 102. MS (ESI): mass calcd. for C₁₉H₁₉ClF₃NO₂, 385.1; m/z found, 386.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.69 (s, 1H), 7.54 (t, J=8.0 Hz, 2H), 7.45 (t, J=7.7 Hz, 1H), 6.76 (dd, J=8.6, 2.4 Hz, 1H), 6.70 (d, J=8.6 Hz, 1H), 6.59 (d, J=2.3 Hz, 1H), 5.29 (q, J=6.4 Hz, 1H), 4.76-4.65 (m, 1H), 3.85 (s, 2H), 3.14 (s, 2H), 2.42 (s, 3H), 1.66 (d, J=6.5 Hz, 3H).

Example 104: (S)-1-Benzyl-3-[5-chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine

Prepared according to general procedure 3 or 4 using the title compound of Example 102. MS (ESI): mass calcd. for C₂₅H₂₃ClF₃NO₂, 461.1; m/z found, 462.3 [M+H]⁺. ¹H NMR (CDCl₃): 7.69 (s, 1H), 7.54 (t, J=7.1 Hz, 2H), 7.45 (t, J=7.7 Hz, 1H), 7.37-7.23 (m, 5H), 6.75 (dd, J=8.6, 2.3 Hz, 1H), 6.69 (d, J=8.6 Hz, 1H), 6.58 (d, J=2.3 Hz, 1H), 5.28 (q, J=6.5 Hz, 1H), 4.80-4.71 (m, 1H), 3.85-3.80 (m, 2H), 3.71 (s, 2H), 3.24-3.14 (m, 2H), 1.66 (d, J=6.5 Hz, 3H).

Example 105: (±)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₇ClF₃NO₂, 371.1; m/z found, 372.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.61 (s, 1H), 7.54 (d, J=7.8 Hz, 2H), 7.51-7.45 (m, 1H), 6.85 (dd, J=8.7, 2.4 Hz, 1H), 6.67 (s, 1H), 6.66 (d, J=7.1 Hz, 1H), 5.31 (q, J=6.4 Hz, 1H), 5.13-5.09 (m, 1H), 4.58-4.30 (m, 4H), 1.67 (d, J=6.5 Hz, 3H).

Example 106: (±)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-1-isopropyl-azetidine

Synthesized from the title compound of Example 105 according to general procedure 3. MS (ESI): mass calcd. for C₂₁H₂₃ClF₃NO₂, 413.1; m/z found, 414.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.68 (s, 1H), 7.54 (t, J=7.6 Hz, 2H), 7.45 (t, J=7.7 Hz, 1H), 6.76 (dd, J=8.6, 2.4 Hz, 1H), 6.69 (d, J=8.6 Hz, 1H), 6.62 (d, J=2.4 Hz, 1H), 5.28 (q, J=6.5 Hz, 1H), 4.75-4.69 (m, 1H), 3.86-3.82 (m, 2H), 3.11-3.04 (m, 2H), 2.40 (td, J=12.4, 6.2 Hz, 1H), 1.65 (d, J=6.5 Hz, 3H), 0.98 (dd, J=6.2, 0.8 Hz, 6H).

Example 107: (±)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-1-cyclobutyl-azetidine

Synthesized from the title compound of Example 105 according to general procedure 3. MS (ESI): mass calcd. for C₂₂H₂₃ClF₃NO₂, 425.1; m/z found, 426.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.67 (s, 1H), 7.55 (t, J=8.7 Hz, 2H), 7.45 (t, J=7.7 Hz, 1H), 6.76 (dd, J=8.6, 2.3 Hz, 1H), 6.69 (d, J=8.6 Hz, 1H), 6.61 (d, J=2.3 Hz, 1H), 5.28 (q, J=6.4 Hz, 1H), 4.78-4.72 (m, 1H), 3.75 (dd, J=8.5, 6.1 Hz, 2H), 3.26-3.09 (m, 3H), 2.07-1.94 (m, 2H), 1.92-1.68 (m, 4H), 1.66 (d, J=6.5 Hz, 3H).

Example 108: (±)-1-Benzyl-3-[5-chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine

Synthesized from the title compound of Example 105 according to general procedure 3. MS (ESI): mass calcd. for C₂₅H₂₃ClF₃NO₂, 461.1; m/z found, 462.0 [M+H]⁺. ¹H NMR (CDC₃): 7.69 (s, 1H), 7.54 (t, J=7.4 Hz, 2H), 7.44 (t, J=7.7 Hz, 1H), 7.37-7.22 (m, 5H), 6.75 (dd, J=8.6, 2.3 Hz, 1H), 6.69 (d, J=8.6 Hz, 1H), 6.58 (d, J=2.3 Hz, 1H), 5.28 (q, J=6.4 Hz, 1H), 4.79-4.73 (m, 1H), 3.86-3.79 (m, 2H), 3.70 (s, 2H), 3.24-3.13 (m, 2H), 1.66 (d, J=6.5 Hz, 3H).

Example 109: (±)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-1-methyl-azetidine

Synthesized from the title compound of Example 105 according to general procedure 5. MS (ESI): mass calcd. for C₁₉H₁₉ClF₃NO₂, 385.1; m/z found, 386.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.69 (s, 1H), 7.54 (t, J=8.5 Hz, 2H), 7.45 (t, J=7.7 Hz, 1H), 6.76 (dd, J=8.6, 2.3 Hz, 1H), 6.70 (d, J=8.6 Hz, 1H), 6.60 (d, J=2.3 Hz, 1H), 5.29 (q, J=6.4 Hz, 1H), 4.74-4.68 (m, 1H), 3.85 (s, 2H), 3.14 (s, 2H), 2.42 (s, 3H), 1.66 (d, J=6.5 Hz, 3H).

Example 110: (±)-3-[5-Bromo-2-[1-(3-trifluoromethoxy-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₇BrF₃NO₃, 431.0; m/z found, 431.9 [M+H]⁺. ¹H NMR (CDCl₃): 7.36 (t, J=8.1 Hz, 1H), 7.27 (d, J=8.1 Hz, 2H), 7.12 (d, J=8.1 Hz, 1H), 6.91 (dd, J=8.6, 2.3 Hz, 1H), 6.70 (d, J=2.3 Hz, 1H), 6.64 (d, J=8.6 Hz, 1H), 5.25 (q, J=6.5 Hz, 1H), 5.01-4.93 (m, 1H), 4.01-3.80 (m, 4H), 1.65 (d, J=6.5 Hz, 3H).

Example 111: (±)-3-[5-Bromo-2-[1-(3-chloro-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₇BrClNO₂, 381.0; m/z found, 382.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.42 (s, 1H), 7.29-7.19 (m, 3H), 6.90 (dd, J=8.6, 2.3 Hz, 1H), 6.69 (d, J=2.3 Hz, 1H), 6.64 (d, J=8.6 Hz, 1H), 5.20 (q, J=6.4 Hz, 1H)), 5.00-4.92 (m, 1H), 3.95-3.80 (m, 4H), 1.64 (d, J=6.5 Hz, 3H).

Example 112: (±)-3-[5-Bromo-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₇BrF₃NO₂, 415.0; m/z found, 416.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.69 (s, 1H), 7.53 (t, J=7.3 Hz, 2H), 7.44 (t, J=7.7 Hz, 1H), 6.89 (dd, J=8.6, 2.3 Hz, 1H), 6.68 (d, J=2.3 Hz, 1H), 6.65 (d, J=8.6 Hz, 1H), 5.29 (q, J=6.5 Hz, 1H), 4.99-4.93 (m, 1H), 3.95-3.92 (m, 2H), 3.87-3.80 (m, 2H), 1.65 (d, J=6.5 Hz, 3H).

Example 113: (R)-3-[5-Bromo-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₇BrF₃NO₂, 415.0; m/z found, 418.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.69 (s, 1H), 7.58-7.50 (m, 2H), 7.45 (t, J=7.7 Hz, 1H), 6.91 (dd, J=8.6, 2.3 Hz, 1H), 6.69 (d, J=2.3 Hz, 1H), 6.66 (d, J=8.6 Hz, 1H), 5.30 (q, J=6.5 Hz, 1H), 4.99-4.93 (m, 1H), 4.01-3.74 (m, 4H), 1.67 (d, J=6.5 Hz, 3H).

Example 114: (±)-3-[5-Chloro-2-[1-(3-chloro-phenyl)-ethoxly]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₇Cl₂NO₂, 337.1; m/z found, 338.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.43 (s, 1H), 7.32-7.17 (m, 3H), 6.76 (dd, J=8.6, 2.4 Hz, 1H), 6.70 (d, J=8.6 Hz, 1H), 6.56 (d, J=2.3 Hz, 1H), 5.20 (q, J=6.5 Hz, 1H), 5.02-4.92 (m, 1H), 3.94 (s, 2H), 3.92-3.78 (m, 2H), 1.65 (d, J=6.5 Hz, 3H).

Example 115: (±)-3-[5-Chloro-2-[1-(3-fluoro-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₇ClFNO₂, 321.1; m/z found, 322.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.35-7.23 (m, 1H), 7.21-7.07 (m, 2H), 7.00-6.91 (m, 1H), 6.71-6.65 (m, 2H), 6.64-6.52 (m, 1H), 5.28-5.18 (m, 1H), 5.05-4.93 (m, 1H), 4.10-3.95 (s, 4H), 1.70-1.60 (s, 3H).

Example 116: (±)-3-[5-Chloro-2-[1-(2-chloro-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₇Cl₂NO₂, 337.1; m/z found, 338.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.55 (dd, J=7.6, 1.8 Hz, 1H), 7.34 (dd, J=7.8, 1.4 Hz, 1H), 7.28-7.14 (m, 2H), 6.73 (dd, J=8.6, 2.4 Hz, 1H), 6.59 (d, J=8.7 Hz, 1H), 6.56 (d, J=2.4 Hz, 1H), 5.66 (q, J=6.4 Hz, 1H), 5.00-4.94 (m, 1H), 4.02-3.81 (m, 4H), 1.64 (d, J=6.4 Hz, 3H).

Example 117: (±)-3-[5-Chloro-2-[1-(4-fluoro-3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₆ClF₄NO₂, 389.1; m/z found, 390.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.68 (dd, J=6.7, 1.9 Hz, 1H), 7.58-7.51 (m, 1H), 7.19-7.14 (m, 1H), 6.78 (dd, J=8.6, 2.4 Hz, 1H), 6.71 (d, J=8.6 Hz, 1H), 6.55 (d, J=2.3 Hz, 1H), 5.27 (q, J=6.4 Hz, 1H), 4.95-4.90 (m, 1H), 3.95-3.84 (m, 4H), 1.65 (d, J=6.5 Hz, 3H).

Example 118: (±)-3-[5-Chloro-2-[1-(3-fluoro-4-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₆ClF₄NO₂, 389.1; m/z found, 390.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.57 (t, J=7.6 Hz, 1H), 7.31-7.22 (m, 2H), 6.77 (dd, J=8.6, 2.4 Hz, 1H), 6.68 (d, J=8.6 Hz, 1H), 6.56 (d, J=2.4 Hz, 1H), 5.26 (q, J=6.5 Hz, 1H), 4.99-4.93 (m, 1H), 3.97-3.80 (m, 4H), 1.65 (d, J=6.5 Hz, 3H).

Example 119: (±)-3-[5-Chloro-2-[1-(3-fluoro-5-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₆ClF₄NO₂, 389.1; m/z found, 390.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.33 (d, J=9.3 Hz, 1H), 7.23 (d, J=8.3 Hz, 1H), 6.79 (dd, J=8.6, 2.3 Hz, 1H), 6.73 (d, J=8.6 Hz, 1H), 6.56 (d, J=2.3 Hz, 1H), 5.28 (q, J=6.5 Hz, 1H), 4.99-4.92 (m, 1H), 7.47 (s, 1H), 4.05-3.74 (m, 4H), 1.66 (d, J=6.5 Hz, 3H).

Example 120: (±)-3-[5-Chloro-2-[1-(3-trifluoromethylsulfanyl-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₇ClF₃NO₂S, 403.1; m/z found, 404.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.70 (s, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.39 (t, J=7.7 Hz, 1H), 6.75 (dd, J=8.6, 2.3 Hz, 1H), 6.68 (d, J=8.6 Hz, 1H), 6.55 (d, J=2.2 Hz, 1H), 5.26 (q, J=6.5 Hz, 1H), 4.99-4.93 (m, 1H), 3.94-3.83 (m, 4H), 1.66 (d, J=6.5 Hz, 3H).

Example 121: (±)-3-[5-Chloro-2-[1-(2-fluoro-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₇ClFNO₂, 321.1; m/z found, 322.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.50 (dt, J=7.6, 1.7 Hz, 1H), 7.24-7.21 (m, 1H), 7.12 (dt, J=7.6, 1.0 Hz, 1H), 7.06-6.99 (m, 1H), 6.75 (dd, J=8.6, 2.3 Hz, 1H), 6.69 (d, J=8.6 Hz, 1H), 6.56 (d, J=2.3 Hz, 1H), 5.60 (q, J=6.4 Hz, 1H), 5.00-4.94 (m, 1H), 4.00-3.79 (m, 4H), 1.67 (d, J=6.4 Hz, 3H).

Example 122: (±)-3-[5-Chloro-2-[1-(2-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₇ClF₃NO₂, 371.1; m/z found, 372.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.85 (d, J=7.9 Hz, 1H), 7.61 (d, J=7.9 Hz, 1H), 7.56 (t, J=7.7 Hz, 1H), 7.36 (t, J=7.6 Hz, 1H), 6.72 (dd, J=8.6, 2.3 Hz, 1H), 6.67 (d, J=8.6 Hz, 1H), 6.54 (d, J=2.3 Hz, 1H), 5.68 (q, J=6.2 Hz, 1H), 5.00-4.94 (m, 1H), 4.01-3.79 (m, 4H), 1.66 (d, J=6.3 Hz, 3H).

Example 123: (±)-3-[5-Chloro-2-[1-(4-chloro-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₇Cl₂NO₂, 337.1; m/z found, 338.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.30 (s, 4H), 6.74 (dd, J=8.6, 2.4 Hz, 1H), 6.65 (d, J=8.6 Hz, 1H), 6.55 (d, J=2.4 Hz, 1H), 5.21 (q, J=6.5 Hz, 1H), 4.99-4.93 (m, 1H), 3.96-3.83 (m, 4H), 1.64 (d, J=6.5 Hz, 3H).

Example 124: (±)-3-[5-Chloro-2-[1-(4-fluoro-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₇ClFNO₂, 321.1; m/z found, 322.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.39-7.29 (m, 2H), 7.06-6.97 (m, 2H), 6.74 (dd, J=8.6, 2.4 Hz, 1H), 6.66 (d, J=8.6 Hz, 1H), 6.55 (d, J=2.4 Hz, 1H), 5.22 (q, J=6.4 Hz, 1H), 4.99-4.93 (m, 1H), 3.99-3.78 (m, 4H), 1.64 (d, J=6.4 Hz, 3H).

Example 125: (±)-3-[1-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-ethyl]-benzonitrile

MS (ESI): mass calcd. for C₁₈H₁₇ClN₂O₂, 328.1; m/z found, 329.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.76 (s, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.57 (td, J=7.7, 1.3 Hz, 1H), 7.45 (t, J=7.7 Hz, 1H), 6.76 (dd, J=8.6, 2.4 Hz, 1H), 6.69 (d, J=8.6 Hz, 1H), 6.56 (d, J=2.4 Hz, 1H), 5.27 (q, J=6.6 Hz, 1H), 5.01-4.95 (m, 1H), 4.02-3.76 (m, 4H), 1.65 (d, J=6.5 Hz, 3H).

Example 126: (±)-3-[5-Chloro-2-[1-(3,4-dichloro-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₆Cl₃NO₂, 371.0; m/z found, 372.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.52 (d, J=2.0 Hz, 1H), 7.40 (d, J=8.3 Hz, 1H), 7.19 (dd, J=8.3, 2.0 Hz, 1H), 6.77 (dd, J=8.6, 2.4 Hz, 1H), 6.69 (d, J=8.6 Hz, 1H), 6.55 (d, J=2.4 Hz, 1H), 5.18 (q, J=6.5 Hz, 1H), 4.99-4.93 (m, 1H), 4.00-3.76 (m, 4H), 1.63 (d, J=6.5 Hz, 3H).

Example 127: (±)-3-[5-Chloro-2-[1-(3-trifluoromethoxy-phenyl)-ethoxy]-phenoxy]azetidine

MS (ESI): mass calcd. for C₁₈H₁₇ClF₃NO₃, 387.1; m/z found, 388.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.36 (t, J=8.1 Hz, 1H), 7.30-7.27 (m, 2H), 7.16-7.08 (m, 1H), 6.76 (dd, J=8.6, 2.4 Hz, 1H), 6.69 (d, J=8.6 Hz, 1H), 6.55 (d, J=2.4 Hz, 1H), 5.25 (q, J=6.4 Hz, 1H), 5.00-4.93 (m, 1H), 3.98-3.77 (m, 4H), 1.65 (d, J=6.5 Hz, 3H).

Example 128: (±)-3-[5-Chloro-2-[1-(3,4-difluoro-phenyl)-ethoxy]-phenoxy]-azetidine trifluoroacetate

MS (ESI): mass calcd. for C₁₇H₁₆ClF₂NO₂, 339.1; m/z found, 340.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.21-7.09 (m, 2H), 7.08-7.02 (m, 1H), 6.85 (dd, J=8.7, 2.4 Hz, 1H), 6.68 (d, J=2.4 Hz, 1H), 6.65 (d, J=8.8 Hz, 1H), 5.20 (q, J=6.4 Hz, 1H), 5.13-5.05 (m, 1H), 4.44-4.32 (m, 4H), 1.62 (d, J=6.4 Hz, 3H).

Example 129: (±)-3-[5-Chloro-2-[1-(2,5-dichloro-phenyl)-ethoxy]-phenoxy]-azetidine trifluoroacetate

MS (ESI): mass calcd. for C₁₇H₁₆Cl₃NO₂, 371.0; m/z found, 372.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.43 (d, J=2.5 Hz, 1H), 7.30 (d, J=8.5 Hz, 1H), 7.19 (dd, J=8.5, 2.5 Hz, 1H), 6.86 (dd, J=8.7, 2.4 Hz, 1H), 6.69 (d, J=2.4 Hz, 1H), 6.57 (d, J=8.8 Hz, 1H), 5.59 (q, J=6.3 Hz 1H), 5.14 (s, 1H), 4.49-4.37 (m, 4H), 1.63 (d, J=6.4 Hz, 3H).

Example 130: (±)-3-[5-Chloro-2-[1-(2,5-difluoro-phenyl)-ethoxy]-phenoxy]-azetidine trifluoroacetate

MS (ESI): mass calcd. for C₁₇H₁₆ClF₂NO₂, 339.1; m/z found, 340.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.43 (d, J=2.5 Hz, 1H), 7.30 (d, J=8.5 Hz, 1H), 7.19 (dd, J=8.5, 2.5 Hz, 1H), 6.86 (dd, J=8.7, 2.4 Hz, 1H), 6.69 (d, J=2.4 Hz, 1H), 6.57 (d, J=8.8 Hz, 1H), 5.59 (q, J=6.3 Hz, 1H), 5.14 (s, 1H), 4.47-4.34 (m, 4H), 1.63 (d, J=6.4 Hz, 3H).

Example 131: 2-[1-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-ethyl]-benzothiazole

MS (ESI): mass calcd. for C₁₈H₁₇ClN₂O₂S, 360.1; m/z found, 361.0 [M+H]⁺. ¹H NMR (CDCl₃): 8.01-7.99 (m, 1H), 7.92-7.86 (m, 1H), 7.48 (ddd, J=8.3, 7.3, 1.3 Hz, 1H), 7.39 (ddd, J=8.3, 7.3, 1.2 Hz, 1H), 6.93 (d, J=8.6 Hz, 1H), 6.80 (dd, J=8.6, 2.4 Hz, 1H), 6.59 (d, J=2.4 Hz, 1H), 5.66 (q, J=6.5 Hz, 1H), 5.01-4.95 (m, 1H), 3.95-3.88 (m, 2H), 3.86-3.80 (m, 2H), 1.86 (d, J=6.5 Hz, 3H).

Example 132: 5-[1-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-ethyl]-thiazole

MS (ESI): mass calcd. for C₁₄H₁₅ClN₂O₂S, 310.1; m/z found, 311.0 [M+H]⁺. ¹H NMR (CDCl₃): 8.77 (s, 1H), 7.73 (s, 1H), 6.83-6.77 (m, 2H), 6.57-6.56 (m, 1H), 5.56 (q, J=6.4 Hz, 1H), 5.02-4.89 (m, 1H), 3.98-3.90 (m, 2H), 3.87-3.75 (m, 2H), 1.77 (d, J=6.4 Hz, 3H).

Example 133: 2-[1-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-ethyl]-thiazole

MS (ESI): mass calcd. for C₁₄H₁₅ClN₂O₂S, 310.1; m/z found, 311.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.74 (d, J=3.2 Hz, 1H), 7.33 (d, J=3.2 Hz, 1H), 6.88 (d, J=8.6 Hz, 1H), 6.81 (dd, J=8.6, 2.3 Hz, 1H), 6.59 (d, J=2.3 Hz, 1H), 5.59 (q, J=6.5 Hz, 1H), 5.02-4.92 (m, 1H), 4.04-3.72 (m, 4H), 1.79 (dd, J=6.4, 2.2 Hz, 3H).

Example 134: 5-[1-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-ethyl]-2,4-dimethyl-thiazole

MS (ESI): mass calcd. for C₁₆H₁₉ClN₂O₂S, 338.1; m/z found, 339.1 [M+H]₊. ¹H NMR (CDCl₃): 6.78 (dd, J=8.5, 2.4 Hz, 1H), 6.70 (d, J=8.6 Hz, 1H), 6.55 (d, J=2.4 Hz, 1H), 5.48 (q, J=6.4 Hz, 1H), 5.00-4.90 (m, 1H), 4.02-3.76 (m, 4H), 2.63 (s, 3H), 2.19 (s, 3H), 1.69 (d, J=6.4 Hz, 3H).

Example 135: (R)-4-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-piperidine

MS (ESI): mass calcd. for C₂₀H₂₁ClF₃NO₂, 399.1; m/z found, 400.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.68 (s, 1H), 7.57-7.52 (m, 2H), 7.45 (t, J=7.7 Hz, 1H), 6.90 (d, J=2.4 Hz, 1H), 6.77 (d, J=8.6, 2.4 Hz, 1H), 6.69 (d, J=8.6 Hz, 1H), 5.30 (q, J=6.4 Hz, 1H), 4.36-4.32 (m, 1H), 3.17 (br s, 2H), 2.74 (br s, 2H), 2.02 (br s, 2H), 1.72 (br s, 2H), 1.64 (d, J=6.4 Hz, 3H).

Example 136: (±)-4-[5-Chloro-2-[1-(3-chloro-phenyl)-ethoxy]-phenoxy]-piperidine

MS (ESI): mass calcd. for C₁₉H₂₁Cl₂NO₂, 349.1; m/z found, 350.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.40 (s, 1H), 7.29-7.19 (m, 3H), 6.89 (d, J=2.4 Hz, 1H), 6.76 (dd, J=8.6, 2.4 Hz, 1H), 6.68 (d, J=8.6 Hz, 1H), 5.21 (q, J=6.4 Hz, 1H), 4.38-4.27 (m, 1H), 3.17 (td, J=7.8, 4.6 Hz, 2H), 2.72 (ddd, J=12.5, 9.3, 3.2 Hz, 2H), 2.09-1.93 (m, 2H), 1.79-1.66 (m, 2H), 1.62 (d, J=6.5 Hz, 3H).

Example 137: (±)-4-[5-Chloro-2-[1-(3-trifluoromethoxy-phenyl)-ethoxy]-phenoxy]-piperidine

MS (ESI): mass calcd. for C₂₀H₂₁ClF₃NO₃, 415.1; m/z found, 416.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.36 (t, J=7.9 Hz, 1H), 7.28 (d, J=8.8 Hz, 2H), 7.12 (d, J=8.0 Hz, 1H), 6.90 (d, J=2.4 Hz, 1H), 6.76 (dd, J=8.6, 2.4 Hz, 1H), 6.68 (d, J=8.6 Hz, 1H), 5.26 (q, J=6.4 Hz, 1H), 4.43-4.24 (m, 1H), 3.22-3.09 (m, 2H), 2.73 (ddd, J=12.5, 9.2, 3.1 Hz, 2H), 2.02 (d, J=9.1 Hz, 2H), 1.72 (dt, J=12.7, 9.0, 2H), 1.63 (d, J=6.4 Hz, 3H).

Example 138: (±)-4-[5-Chloro-2-[1-(2-fluoro-phenyl)-ethoxy]-phenoxy]-piperidine

MS (ESI): mass calcd. for C₁₉H₂₁ClFNO₂, 349.1; m/z found, 350.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.50 (dt, J=7.6, 1.7 Hz, 1H), 7.26-7.20 (m, 1H), 7.12 (dt, J=7.5, 1.0 Hz, 1H), 7.02 (ddd, J=10.2, 8.2, 1.1 Hz, 1H), 6.89 (d, J=2.4 Hz, 1H), 6.76 (dd, J=8.7, 2.4 Hz, 1H), 6.69 (d, J=8.7 Hz, 1H), 5.59 (q, J=6.4 Hz, 1H), 4.38-4.27 (m, 1H), 3.16 (td, J=9.8, 4.6 Hz, 2H), 2.71 (ddd, J=12.4, 9.3, 3.1 Hz, 2H), 2.01 (ddd, J=13.2, 5.0, 3.0 Hz, 2H), 1.72 (ddt, J=11.7, 8.3, 3.1 Hz, 2H), 1.64 (d, J=6.4 Hz, 3H).

Example 139: (R,S)-3-[5-Chloro-2-[1-((R)-3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-piperidine

MS (ESI): mass calcd. for C₂₀H₂₁ClF₃NO₂, 399.1; m/z found, 400.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.68 (s, 1H), 7.57-7.53 (m, 2H), 7.48-7.44 (m, 1H), 6.92 (dd, J=2.4, 1.1 Hz, 1H), 6.79-6.76 (m, 1H), 6.69 (dd, J=8.6, 6.1 Hz, 1H), 5.33-5.26 (m, 1H), 4.24-4.17 (m, 1H), 3.14-3.11 (m, 1H), 2.89-2.73 (m, 3H), 2.05-1.98 (m, 1H), 1.87-1.73 (m, 2H), 1.64 (d, J=6.5 Hz, 3H), 1.54-1.45 (m, 1H).

Example 140: (±)-3-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-propoxy]-phenoxy]-azetidine

MS (ESI): MS (ESI): mass calcd. for C₁₉H₁₉ClF₃NO₂, 385.1; m/z found, 386.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.66 (s, 1H), 7.52 (t, J=7.5 Hz, 2H), 7.44 (t, J=7.7 Hz, 1H), 6.73 (dd, J=8.6, 2.4 Hz, 1H), 6.65 (d, J=8.6 Hz, 1H), 6.54 (d, J=2.4 Hz, 1H), 5.05-5.00 (m, 1H), 4.99-4.92 (m, 1H), 4.01-3.72 (m, 4H), 2.31-1.97 (m, 1H), 1.97-1.83 (m, 1H), 1.02 (t, J=7.4 Hz, 3H).

Example 141: (±)-4-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-propoxy]-phenoxy]-piperidine

MS (ESI): mass calcd. for C₂₁H₂₃ClF₃NO₂, 413.1; m/z found, 414.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.61 (s, 1H), 7.51 (dd, J=7.4, 4.4 Hz, 2H), 7.47-7.40 (m, 1H), 6.88 (d, J=2.5 Hz, 1H), 6.72 (dd, J=8.6, 2.5 Hz, 1H), 6.61 (d, J=8.7 Hz, 1H), 5.05 (t, J=6.3 Hz, 1H), 4.37-4.28 (m, 1H), 3.23-3.10 (m, 2H), 2.71 (ddd, J=12.6, 9.4, 3.2 Hz, 2H), 2.13-1.97 (m, 3H), 1.96-1.84 (m, 1H), 1.76-1.65 (m, 2H), 0.98 (t, J=7.4 Hz, 3H).

Example 142: 3-[5-Bromo-2-(2-fluoro-1-phenyl-ethoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₇BrFNO₂, 365.0; m/z found, 366.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.41-7.30 (m, 5H), 6.88 (dd, J=8.6, 2.3 Hz, 1H), 6.69 (dd, J=13.3, 5.4 Hz, 2H), 5.35 (ddd, J=14.3, 7.7, 3.3 Hz, 1H), 5.00-4.93 (m, 1H), 4.75 (ddd, J=48.0, 10.1, 7.7 Hz, 1H), 4.59 (ddd, J=46.7, 10.1, 3.4 Hz, 1H), 3.93-3.79 (m, 4H).

Example 143: 3-[5-Chloro-2-(2-fluoro-1-phenyl-ethoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₇ClFNO₂, 321.1; m/z found, 322.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.42-7.31 (m, 5H), 6.75-6.71 (m, 2H), 6.56 (s, 1H), 5.35 (ddd, J=14.3, 7.7, 3.3 Hz, 1H), 5.00 (s, 1H), 4.75 (ddd, J=48.0, 10.0, 7.7, Hz, 1H), 4.59 (ddd, J=46.7, 10.1, 3.3 Hz, 1H), 4.26-3.53 (m, 4H).

Example 144: (±)-4-[5-Chloro-2-(2-fluoro-1-phenyl-ethoxy)-phenoxy]-piperidine

MS (ESI): mass calcd. for C₁₉H₂₁ClFNO₂, 349.1; m/z found, 350.1 [M+H]⁺. ¹H NMR (CDCl₃): δ 7.45-7.28 (m, 5H), 6.90 (d, J=2.2 Hz, 1H), 6.77-6.67 (m, 2H), 5.36 (ddd, J=14.5, 7.6, 3.3 Hz, 1H), 4.80-4.50 (m, 2H), 4.35 (dt, J=12.3, 4.0 Hz, 1H), 3.14 (dd, J=12.0, 4.9 Hz, 2H), 2.70 (dd, J=11.9, 9.7 Hz, 2H), 2.00 (dd, J=7.9, 3.9 Hz, 2H), 1.77-1.62 (m, 2H).

Example 145: (±)-3-[5-Chloro-2-(1-phenyl-ethoxy)-phenoxy]-azetidine

Step A: Preparation of 1-[3-(5-Chloro-2-hydroxy-phenoxy)-azetidin-1-yl]-2,2,2-trifluoro-ethanone

To 3-(5-Chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (0.80 g, 2.7 mmol) in EtOAc (2 mL) was added 4M HCl in dioxane (5 mL). After 18 h, EtOAc was added and the resulting white solid filtered to give 2-(azetidin-3-yloxy)-4-chloro-phenol hydrochloride as a white solid. To a CH₂Cl₂ (25 mL) solution of this compound was added Et₃N (0.30 g, 0.42 mL, 3.0 mmol) and TFAA (0.58 g, 0.38 mL, 2.8 mmol). After 18 h, H₂O was added and the reaction extracted with CH₂Cl₂ (2×). The combined organics were dried and concentrated to give 0.54 g (74% yield 2 steps) of the title compound as a brown oil that was used in the next step without further purification.

Step B: Preparation of (±)-1-[3-[5-Chloro-2-(1-phenyl-ethoxy)-phenoxy]-azetidin-1-yl]-2,2,2-trifluoro-ethanone

To the title compound of Step A (0.17 g, 0.56 mmol) in DMF (3 mL) was added Cs₂CO₃ (0.25 g, 0.80 mmol), KI (0.09 g, 0.55 mmol) and (1-bromoethyl)-benzene (0.10 g, 0.08 mL, 0.56 mmol). After 15 h, H₂O was added and the mixture extracted with EtOAc (2×). The combined organics were washed with brine and dried. Silica gel chromatography (5-25% EtOAc in hexanes) gave 0.14 g (64%) of the title compound. ¹H NMR (CDCl₃): 7.37-7.27 (m, 5H), 6.82 (dd, J=8.7, 2.4 Hz, 1H), 6.72 (d, J=2.4 Hz, 1H), 6.60 (d, J=2.4 Hz, 1H), 5.2 (q, J=6.5 Hz, 1H), 5.0-4.9 (m, 1H), 4.75-4.69 (m, 1H), 4.52-4.42 (m, 2H), 4.32-4.21 (m, 1H), 1.67 (d, J=6.4 Hz, 3H).

Step C: Preparation of (±)-3-[5-Chloro-2-(1-phenyl-ethoxy)-phenoxy]-azetidine

To the title compound of Step B in MeOH (4 mL) was added K₂CO₃ (0.10 g, 0.72 mmol). After 15 h, H₂O was added and the mixture extracted with EtOAc (2×). The combined organics were dried and concentrated. Silica gel chromatography (1-7 2M NH₃/MeOH in CH₂Cl₂) gave 0.75 g (68% yield) of the title compound. MS (ESI): mass calcd. for C₁₇H₁₈ClNO₂, 303.10; m/z found, 304.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.38-7.31 (m, 4H), 7.28-7.24 (m, 1H), 6.72 (dd, J=8.6, 2.4 Hz, 1H), 6.67 (d, J=8.6 Hz, 1H), 6.55 (d, J=2.4 Hz, 1H), 5.23 (q, J=6.4 Hz, 1H), 4.99-4.93 (m, 1H), 3.95-3.81 (m, 4H), 1.66 (d, J=6.5 Hz, 3H).

Example 146: (±)-3-[5-Chloro-2-[1-(5-trifluoromethyl-furan-2-yl)-ethoxy]-phenoxy]-azetidine

Step A: Preparation of 1-(5-Trifluoromethyl-furan-2-yl)-ethanol

To 5-trifluoromethyl-furan-2-carbaldehyde (0.76 g, 4.6 mmol) in THF (20 mL) at 0° C. was added MeMgBr (3M in Et₂O, 3 mL, 6 mmol) dropwise over 1 h. After an additional 1 h, 1 saturated NH₄Cl (aq.) was added and the mixture extracted with EtOAc (2×). The combined organics were washed with brine and dried to give 0.81 g (97%) of the title compound. ¹H NMR (CDCl₃): 6.74-6.73 (m, 1H), 6.32-6.31 (m, 1H), 4.91 (q, J=6.5 Hz, 1H), 1.57 (d, J=6.6 Hz, 3H).

Step B: Preparation of 1-(3-[5-Chloro-2-[1-(5-trifluoromethyl-furan-2-yl)-ethoxy]-phenoxy]-azetidin-1-yl)-2,2,2-trifluoro-ethanone

Prepared from the title compound of Step A and the title compound of Example 145 Step A using general procedure 7. ¹H NMR (CDCl₃): 6.94 (dd, J=8.6, 2.3 Hz, 1H), 6.88 (dd, J=8.7, 1.4 Hz, 1H), 6.73 (m, 1H), 6.62 (d, J=2.3 Hz, 1H), 6.33 (d, J=3.3 Hz, 1H), 5.27-5.22 (m, 1H), 5.01-4.94 (m, 1H), 4.76-4.69 (m, 1H), 4.52-4.44 (m, 2H), 4.27-4.21 (m, 1H), 1.74 (d, J=6.6 Hz, 3H).

Step C: Preparation of (±)-3-[5-Chloro-2-[1-(5-trifluoromethyl-furan-2-yl)-ethoxy]-phenoxy]-azetidine

Prepared from the title compound of Step B according to Example 145 Step C. MS (ESI): mass calcd. for C₁₆H₁₅ClF₃NO₃, 361.1; m/z found, 362.0 [M+H]⁺. ¹H NMR (CDC₃): 6.84-6.79 (m, 2H), 6.72-6.71 (m, 1H), 6.57 (d, J=1.9 Hz, 1H), 6.32 (d, J=3.4 Hz, 1H), 5.24 (q, J=6.6 Hz, 1H), 4.98-4.92 (m, 1H), 3.93-3.82 (m, 4H), 1.72 (d, J=6.6 Hz, 3H).

Example 147: 3-[5-Chloro-2-(1-phenyl-propoxy)-phenoxy]-azetidine

Synthesized according to Example 146 using 1-phenyl-propan-1-ol. MS (ESI): mass calcd. for C₁₈H₂₀ClNO₂, 317.1; m/z found, 318.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.33-7.23 (m, 5H), 6.70 (dd, J=8.6, 2.4 Hz, 1H), 6.62 (d, J=8.6 Hz, 1H), 6.54 (d, J=2.3 Hz, 1H), 4.97-4.92 (m, 2H), 4.03-3.78 (m, 4H), 2.11-2.02 (m, 1H), 1.95-1.85 (m, 1H), 1.01 (t, J=7.4 Hz, 3H).

Example 148: 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-2-phenyl-ethanol

Step A: Preparation of 3-[5-Chloro-2-(methoxycarbonyl-phenyl-methoxy)-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester

To 3-(5-Chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (1.1 g, 3.7 mmol) in DMF (18 mL) was added Cs₂CO₃ (1.5 g, 4.4 mmol) and bromophenylacetic acid methyl ester (0.92 g, 0.63 mL, 4.0 mmol). After 15 h, H₂O was added and the mixture extracted with EtOAc (2×). The combined organics were washed with brine and dried. Silica gel chromatography (5-25% EtOAc in hexanes) gave 1.6 g (96%) of the title compound. ¹H NMR (CDCl₃): 7.55-7.33 (m, 2H), 7.43-7.36 (m, 3H), 6.85 (d, J=1.2, 2H), 6.51 (t, J=1.2 Hz, 1H), 5.58 (s, 1H), 4.91-4.85 (m, 1H), 4.31-4.26 (m, 2H), 3.98-3.93 (m, 2H), 3.89-3.74 (m, 3H), 1.46 (s, 9H).

Step B: Preparation of 3-[5-Chloro-2-(methoxycarbonyl-phenyl-methoxy)-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester

To the title compound of Step A (0.22 g, 0.50 mmol) in THF at 0° C. was added LiBH₄ (2M in THF, 0.4 mL, 0.8 mmol). After 2 h, 1N KHSO₄ (aq.) was added and the mixture extracted with EtOAc (2×). The combined organic layers were washed with brine and dried. Silica gel chromatography (5-25% EtOAc in hexanes) gave 0.17 g (82%) of the title compound. ¹H NMR (CDCl₃): 7.36-7.30 (m, 5H), 6.75 (dd, J=8.6, 2.3 Hz, 1H), 6.68 (d, J=8.7 Hz, 1H), 6.51 (d, J=2.3 Hz, 1H), 5.09 (dd, J=8.7, 3.4 Hz, 1H), 4.90-4.85 (m, 1H), 4.35-4.30 (m, 2H), 4.15-3.94 (m, 4H), 3.80-3.77 (m, 1H), 1.47 (s, 9H).

Step C: Preparation of 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-2-phenyl-ethanol

Prepared from the title compound of Step B according to general procedure 1. MS (ESI): mass calcd. for C₁₇H₁₈ClNO₃, 319.1; m/z found, 320.1 [M+H]⁺. ¹H NMR (DMSO-D₆): 7.40 (m, 5H), 6.94-6.69 (m, 3H), 5.32-5.28 (m, 1H), 5.11-4.79 (m, 2H), 3.80-3.75 (m, 3H), 3.61 (dd, J=11.4, 4.1 Hz, 1H), 3.54-3.20 (m, 2H).

Example 149: [2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-phenyl-acetic acid hydrochloride

Step A: Preparation of 3-[2-(Carboxy-phenyl-methoxy)-5-chloro-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester

To the title compound of Example 148 Step A (0.16 g, 0.36 mmol) in MeOH (3 mL) was added 1N NaOH (3 mL). After 18 h, the solution was acidified with 1N KHSO₄ and extracted with EtOAc (2×). The combined organics were washed with brine and dried to give 0.16 g (>98%) of the title compound. ¹H NMR (CDCl₃): 8.56-8.19 (broad s, 1H), 7.55-7.51 (m, 2H), 7.41-7.36 (m, 3H), 6.85-6.84 (m, 2H), 6.54 (s, 1H), 5.55 (s, 1H), 4.88-4.83 (m, 1H), 4.29-4.24 (m, 2H), 4.06-3.97 (m, 2H), 1.44 (s, 9H).

Step B: Preparation of [2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-phenyl-acetic acid hydrochloride

Prepared from the title compound of Step A according to general procedure 1. MS (ESI): mass calcd. for C₁₇H₁₆ClNO₄, 333.1; m/z found, 334.1 [M+H]⁺. ¹H NMR (DMSO-D₆): 13.3 (s, 1H), 9.27 (s, 2H), 7.58-7.56 (m, 2H), 7.46-7.37 (m, 3H), 7.05-6.99 (m, 2H), 6.96 (d, J=2.2 Hz, 1H), 5.86 (s, 1H), 5.11-5.06 (m, 1H), 4.45-4.37 (m, 2H), 4.05-3.98 (m, 2H).

Example 150: (±)-3-[5-Chloro-2-(6-fluoro-indan-1-yloxy)-phenoxy]-azetidine

Step A: Preparation of (±)-6-fluoro-indan-1-ol

To a solution of 6-fluoro-indan-1-one (0.50 g, 3.3 mmol) in DCE (10 mL) and MeOH (10 mL) was added NaBH₄ (0.25 g, 6.6 mmol). After 30 min the reaction was quenched with H₂O (10 mL) and extracted with CH₂Cl₂ (3×20 mL). The organic layers were combined and dried to give the title compound (0.49 g, 97%). MS (ESI): mass calcd. for C₉H₇FO, 150.1; m/z found, 151.4 [M+H]⁺. ¹H NMR (CDCl₃): 7.23-7.13 (m, 1H), 7.09 (dd, J=8.6, 2.5 Hz, 1H), 6.99-6.90 (m, 1H), 5.21 (t, J=6.3 Hz, 1H), 3.13-2.91 (m, 1H), 2.85-2.68 (m, 1H), 2.63-2.44 (m, 1H), 2.09-1.74 (m, 2H).

Step B: Preparation of 1-[3-[5-Chloro-2-(6-fluoro-indan-1-yloxy)-phenoxy]-azetidin-1-yl]-2,2,2-trifluoro-ethanone

Prepared from the title compound of Step A and the title compound of Example 145 Step A according to the general procedure 7.

Step C: Preparation of 3-[5-Chloro-2-(6-fluoro-indan-1-yloxy)-phenoxy]-azetidine

Prepared from the title compound of Step B using general procedure 2. MS (ESI): mass calcd. for C₁₈H₁₇ClFNO₂, 333.1; m/z found, 334.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.23 (dd, J=8.2, 5.0 Hz, 1H), 7.10-6.87 (m, 4H), 6.65 (s, 1H), 5.68-5.53 (m, 1H), 4.94 (s, 1H), 4.15-4.06 (m, 4H), 3.19-2.99 (m, 1H), 2.97-2.66 (m, 1H), 2.67-2.43 (m, 1H), 2.40-2.17 (m, 1H).

Unless otherwise specified the compounds in Examples 151-161 were prepared according to Example 150 using the appropriately substituted phenol and alcohol.

Example 151: (±)-3-[5-Bromo-2-(indan-1-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₈BrNO₂, 359.1; m/z found, 360.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.40-7.16 (m, 4H), 7.11 (d, J=8.5 Hz, 1H), 7.05-6.90 (m, 2H), 5.67 (d, J=3.4 Hz, 1H), 4.05-3.84 (m, 2H), 3.82-3.52 (m, 2H), 3.24-3.10 (m, 1H), 2.93 (d, J=4.5 Hz, 1H), 2.65-2.43 (m, 1H), 2.34-2.17 (m, 2H).

Example 152: (±)-3-[5-Bromo-2-(5-chloro-indan-1-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₇BrClNO₂, 393.0; m/z found, 394.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.36-7.12 (m, 4H), 7.00-6.87 (m, 1H), 6.79 (s, 1H), 5.65 (s, 1H), 4.98-4.74 (m, 1H), 4.46-4.29 (m, 1H), 4.29-4.04 (m, 2H), 3.25-3.10 (m, 1H), 3.03-2.83 (m, 1H), 2.60-2.46 (m, 1H), 2.36-2.20 (m, 2H).

Example 153: (±)-3-[5-Bromo-2-(6-chloro-indan-1-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₇BrClNO₂, 393.0; m/z found, 394.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.42-7.09 (m, 5H), 7.02-6.83 (m, 1H), 5.62 (s, 1H), 4.38 (s, 1H), 4.27-3.90 (m, 2H), 3.73-3.54 (m, 1H), 3.12 (s, 1H), 2.90 (s, 1H), 2.53 (s, 1H), 2.35-2.14 (m, 2H).

Example 154: (±)-3-[5-Bromo-2-(5-fluoro-indan-1-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₇BrFNO, 377.0; m/z found, 378.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.23 (d, J=5.2, 1H), 7.13-7.03 (m, 1H), 6.98-6.79 (m, 4H), 4.95-4.68 (m, 1H), 4.37-3.96 (m, 4H), 3.08 (s, 1H), 2.86 (s, 1H), 2.53-2.38 (m, 1H), 2.31-2.11 (m, 2H).

Example 155: (±)-3-[5-Bromo-2-(5-methyl-indan-1-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₉H₂₀BrNO₂, 373.1; m/z found, 374.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.25-7.10 (m, 4H), 7.04-6.78 (m, 2H), 5.65 (s, 2H), 4.31 (s, 1H), 4.12 (s, 2H), 3.10 (s, 1H), 2.89 (s, 1H), 2.46 (s, 2H), 2.35 (d, J=6.6 Hz, 4H).

Example 156: (±)-3-[5-Bromo-2-(6-methyl-indan-1-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₉H₂₀BrNO₂, 373.1; m/z found, 374.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.36-7.18 (m, 3H), 7.08 (d, J=8.2, 1H), 7.02-6.92 (m, 2H), 5.67 (d, J=3.4 Hz, 1H), 4.02-3.84 (m, 2H), 3.80-3.53 (m, 2H), 3.24-3.10 (m, 1H), 2.93 (d, J=4.5 Hz, 1H), 2.65-2.46 (m, 1H), 2.37-2.18 (m, 5H).

Example 157: (±)-3-[5-Bromo-2-(6-trifluoromethyl-indan-1-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₉H₁₇BrF₃NO₂, 427.1; m/z found, 429.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.69-7.35 (m, 3H), 7.07 (dd, J=8.5, 2.3 Hz, 1H), 6.91 (d, J=8.5 Hz, 1H), 6.76 (d, J=2.3 Hz, 1H), 5.72-5.56 (m, 1H), 4.95 (s, 1H), 3.91 (s, 4H), 3.21 (d, J=9.4 Hz, 1H), 3.07-2.85 (m, 1H), 2.61-2.46 (m, 1H), 2.42-2.22 (m, 1H).

Example 158: (±)-3-[5-Chloro-2-(6-methyl-indan-1-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₉H₂₀ClNO₂, 329.1; m/z found, 330.4 [M+H]⁺. ¹H NMR (CDCl₃): 7.22-7.08 (m, 3H), 7.02-6.89 (m, 2H), 6.67-6.60 (m, 1H), 5.63 (dd, J=6.5, 4.1 Hz, 1H), 4.96-4.86 (m, 1H), 4.04-3.72 (m, 4H), 3.21-3.02 (m, 1H), 2.94-2.77 (m, 1H), 2.57-2.40 (m, 1H), 2.33 (d, J=8.2 Hz, 3H), 2.29-2.17 (m, 1H).

Example 159: (±)-3-[5-Chloro-2-(6-chloro-indan-1-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₇Cl₂NO₂, 349.1; m/z found, 350.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.38-7.19 (m, 3H), 7.06-6.93 (m, 2H), 6.76-6.59 (m, 1H), 5.74-5.54 (m, 1H), 5.05-4.78 (m, 1H), 4.30-3.89 (m, 3H), 3.13 (d, J=8.2 Hz, 1H), 2.91 (d, J=5.1 Hz, 1H), 2.63-2.45 (m, 1H), 2.27 (s, 1H), 2.19 (s, 1H).

Example 160: 3-[5-Chloro-2-(6-trifluoromethyl-indan-1-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₉H₁₇ClF₃NO₂, 383.1; m/z found, 384.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.74-7.40 (m, 3H), 7.03-6.88 (m, 2H), 6.65 (d, J=2.2 Hz, 1H), 5.73-5.59 (m, 1H), 4.99 (s, 1H), 4.33-3.65 (m, 2H), 3.23 (s, 1H), 3.01 (s, 2H), 2.68-2.48 (m, 2H), 2.44-2.31 (m, 1H).

Example 161: 3-[5-Chloro-2-(1,2,3,4-tetrahydro-naphthalen-1-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₉H₂₀ClNO₂, 329.1; m/z found, 330.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.29-7.13 (m, 4H), 7.01 (d, J=8.7 Hz, 3H), 5.27 (s, 1H), 4.96-4.71 (m, 1H), 4.08 (s, 3H), 2.91 (s, 1H), 2.79 (s, 1H), 2.19-2.04 (m, 4H), 1.86 (s, 1H).

Example 162: 3-[5-Bromo-2-(5-tert-butyl-indan-1-yloxy)-phenoxy]-azetidine

Step A: Preparation of 1-(4-tert-Butyl-phenyl)-3-chloro-propan-1-one

To a solution of tert-butyl benzene (1.0 g, 7.5 mmol) and 3-chloropropionyl chloride (0.7 mL, 7.5 mmoL) in CH₂Cl₂ (20 mL) was added dropwise to a suspension of AlCl₃ (1.1 g, 8.2 mmol) in CH₂Cl₂ (10 mL) at 0° C. The reaction was allowed to warm to rt. After 15 h, the reaction was quenched with H₂O (10 mL) and extracted with CH₂Cl₂ (2×20 mL). The organic layers were combined and dried to give the title compound that was used without further purification (1.3 g).

Step B.: Preparation of 5-tert-butyl-indan-1-one

The title compound of Step A (1.3 g, 5.8 mmol) was dissolved in conc. H₂SO₄ (10 mL) and heated at 95° C. for 3 h. The reaction mixture was cooled to rt, poured onto ice, and extracted with Et₂O (3×25 mL). The combined organic extracts were washed with sat'd NaHCO₃ (aq.) and dried to provide the title compound (0.74 g, 68%). MS (ESI): mass calcd. for C₁₃H₁₆O, 188.1; m/z found, 189.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.67-7.58 (m, 1H), 7.44-7.32 (m, 2H), 3.09-3.02 (m, 2H), 2.65-2.68 (m, 2H), 1.27 (d, J=8.5 Hz, 9H).

Step B.: Preparation of 3-[5-Bromo-2-(5-tert-butyl-indan-1-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₂₂H₂₆BrNO₂, 415.1; m/z found, 418.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.38-7.13 (m, 4H), 7.08-6.84 (m, 2H), 5.71 (s, 1H), 4.32 (s, 2H), 3.71-3.50 (m, 2H), 3.14 (s, 1H), 2.94 (s, 1H), 2.53 (s, 1H), 2.24 (s, 2H), 1.43-1.20 (m, 9H).

Example 163: 3-[5-Chloro-2-(tetrahydro-furan-3-ylmethoxy)-phenoxy]-azetidine

A mixture of 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (0.5 mmol), tetrahydro-furan-3-yl-methanol (0.5 mmol), and cyanomethylenetri-n-butylphosphorane (0.5 mmol) in toluene (3 mL) was heated at 120° C. in a microwave reactor for 1 h. The mixture was cooled to rt and purified via PTLC providing 3-[5-chloro-2-(tetrahydro-furan-3-ylmethoxy)-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester (120 mg). To this compound was added CH₂Cl₂ (20 mL) and TFA (3 mL). After 4 h at rt the mixture was concentrated to give the title compound (161 mg). MS (ESI): mass calcd. for C₁₄H₁₈ClNO₃, 283.1; m/z found, 284.0 [M+H]⁺. ¹H NMR (MeOD): 7.05-6.96 (m, 2H), 6.88 (d, J=1.9 Hz, 1H), 5.15-5.05 (m, 1H), 4.57-4.48 (m, 2H), 4.28-4.19 (m, 2H), 4.04-3.88 (m 4H), 3.82-3.70 (m 2H), 2.82-2.70 (m, 1H), 2.20-2.09 (m, 1H), 1.84-1.73 (m, 1H).

The compounds in Examples 164-174 were prepared according to Example 163 with the appropriate alcohols.

Example 164: 3-[5-Chloro-2-(1,2,3,4-tetrahydro-naphthalen-2-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₉H₂₀ClNO₂, 329.1; m/z found, 330.0 [M+H]⁺. ¹H NMR (MeOD): 7.18-6.90 (m, 7H), 4.98-4.89 (m, 1H), 4.87-4.78 (m, 1H), 4.35-4.25 (m, 2H), 4.12-3.95 (m, 2H), 3.30-2.80 (m, 4H), 2.18-2.02 (m, 2H).

Example 165: 3-[5-Chloro-2-(chroman-2-ylmethoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₉H₂₀ClNO₃, 345.1; m/z found, 346.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.13-6.75 (m, 7H), 5.15-4.98 (m, 1H), 4.55-4.09 (m, 7H), 3.00-2.75 (m, 2H), 2.18-1.85 (m, 2H).

Example 166: 3-[5-Chloro-2-(tetrahydro-furan-2-ylmethoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₄H₁₈ClNO₃, 283.1; m/z found, 284.0 [M+H]⁺. ¹H NMR (MeOD): 7.05-6.86 (m, 3H), 5.12-5.02 (m, 1H), 4.60-4.46 (m, 2H), 4.32-4.20 (m, 3H), 4.09-4.00 (m, 1H), 3.95-3.87 (m, 2H), 3.86-3.70 (m, 1H), 2.20-1.90 (m, 3H), 1.80-1.68 (m, 1H).

Example 167: 3-[5-Chloro-2-(chroman-3-ylmethoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₉H₂₀ClNO₃, 345.1; m/z found, 346.1 [M+H]⁺. ¹H NMR (MeOD): 7.15-6.63 (m, 7H), 5.15-4.98 (m, 1H), 4.60-3.90 (m, 8H), 3.10-2.93 (m, 1H), 2.78-2.50 (m, 2H).

Example 168: 3-[5-Chloro-2-(2-methoxy-2-phenyl-ethoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₂₀ClNO₃, 333.1; m/z found, 334.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.45-7.25 (m, 5H), 7.04-6.88 (m, 3H), 5.05-4.96 (m, 1H), 4.63-4.57 (m, 1H), 4.53-4.42 (m, 2H), 4.26-4.05 (m, 4H), 4.33 (s, 3H).

Example 169: 3-[5-Chloro-2-(2,3-dihydro-benzofuran-2-ylmethoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₈ClNO₃, 331.1; m/z found, 332.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.20-6.66 (m, 7H), 5.20-5.05 (m, 1H), 4.98-4.88 (m, 1H), 4.35-4.03 (m, 6H), 3.42-3.32 (m, 1H), 3.12-3.03 (m, 1H).

Example 170: 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-1,3-dimethyl-1H-pyrazole

MS (ESI): mass calcd. for C₁₅H₁₈ClN₃O₂, 307.1; m/z found, 308.1 [M+H]⁺. ¹H NMR (MeOD): 7.12 (d, J=8.7 Hz, 1H), 7.00 (dd, J=8.7, 2.1 Hz, 1H), 6.87 (d, J=2.1 Hz, 1H), 6.17 (s, 1H), 5.13-5.05 (m, 3H), 4.48-4.39 (m, 2H), 4.18-4.12 (m, 2H), 3.85 (s, 3H), 2.20 (s, 3H).

Example 171: 3-[5-Chloro-2-(2-phenoxy-ethoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₈ClNO₃, 319.1; m/z found, 320.0 [M+H]⁺. ¹H NMR (MeOD): 7.34-7.26 (m, 2H), 7.12-6.92 (m, 6H), 5.14-4.95 (m, 2H), 4.83-4.74 (m, 1H), 4.48-4.42 (m, 1H), 4.39-4.30 (m, 4H), 4.24-4.16 (m, 1H).

Example 172: 3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-phenyl-azetidine

Prepared by the procedure of Example 163 using 5-bromo-2-(3-fluoro-benzyloxy)-phenol and 1-phenyl-azetidin-3-ol. MS (ESI): mass calcd. for C₂₂H₁₉BrFNO₂, 427.1; m/z found, 428.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.34-6.47 (m, 12H), 5.11-5.03 (m, 3H), 4.36-4.28 (m, 2H), 3.98-3.91 (m, 2H).

Example 173: 3-[5-Chloro-2-(indan-2-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₈ClNO₂, 315.1; m/z found, 316.1 [M+H]⁺. ¹H NMR (MeOD): 7.35-7.06 (m, 6H), 6.93-6.90 (m, 1H), 5.28-5.21 (m, 1H), 4.86-4.78 (m, 1H), 4.28-4.18 (m, 2H), 4.08-3.98 (m, 2H), 3.42-3.35 (m, 2H), 3.18-3.08 (m, 2H).

Example 174: 3-[5-Bromo-2-(indan-2-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₈BrNO₂, 359.1; m/z found, 359.9 [M+H]⁺. ¹H NMR (MeOD): 7.33-7.02 (m, 7H), 5.28-5.21 (m, 1H), 4.86-4.78 (m, 1H), 4.28-4.16 (m, 2H), 4.08-3.98 (m, 2H), 3.42-3.35 (m, 2H), 3.18-3.08 (m, 2H).

Example 175: 3-[5-Chloro-2-(5-fluoro-indan-2-yloxy)-phenoxy]-azetidine

Step A: Preparation of 2-Bromo-5-fluoro-indan-1-one

To the solution of 5-fluoro-indan-1-one (10 mmol) in MeOH/CH₂Cl₂ (40 mL/120 mL) was added Bu₄NBr₃ (11 mmol). The mixture was stirred at 25° C. for 16 h, concentrated and partitioned between CH₂Cl₂/H₂O (150 mL/80 mL). The organic layer was concentrated and purified providing the title compound (2 g).

Step B: Preparation of 3-[5-Chloro-2-(5-fluoro-indan-2-yloxy)-phenoxy]-azetidine

The mixture of 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (0.5 mmol), the title compound of Step A (0.5 mmol), and K₂CO₃ (1 mmol) in acetonitrile (3 mL) was heated at 100° C. in a microwave reactor for 1 h. The mixture was cooled to rt and purified via PTLC providing the title compound (150 mg). To this product was added DCE (5 mL), Et₃SiH (1 mL) and TFA (3 mL). The mixture was stirred at 80° C. for 16 h. After concentration, the title compound was obtained (91 mg). MS (ESI): mass calcd. for C₁₈H₁₇ClFNO₂, 333.1; m/z found, 334.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.20-7.13 (m, 1H), 6.96-6.60 (m, 5H), 5.18-5.08 (m, 1H), 4.93-4.83 (m, 1H), 3.98-3.70 (m, 4H), 3.38-3.05 (m, 4H).

The compounds in Examples 176-178 were prepared according to Example 175 using the appropriately substituted indanone.

Example 176: 3-[5-Chloro-2-(5-chloro-indan-2-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₇Cl₂NO₂, 349.1; m/z found, 350.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.26-6.63 (m, 6H), 5.20-5.05 (m, 1H), 4.93-4.83 (m, 1H), 4.10-3.85 (M, 4H), 3.45-3.05 (m, 4H).

Example 177: 3-[5-Chloro-2-(5-methoxy-indan-2-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₉H₂₀ClNO₃, 345.1; m/z found, 346.0 [M+H]⁺. ¹H NMR (MeOD): 7.15 (d, J=8.2 Hz, 1H), 7.08-7.03 (m, 2H), 6.94-6.73 (m, 3H), 5.25-5.17 (m, 1H), 4.90-4.81 (m, 1H), 4.80-4.70 (m, 2H), 4.12-4.02 (m, 2H), 3.77 (s, 3H), 3.37-3.24 (m, 2H), 3.12-2.98 (m, 2H).

Example 178: 3-[5-Chloro-2-(4-methoxy-indan-2-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₉H₂₀ClNO₃, 345.1; m/z found, 346.1 [M+H]⁺. ¹H NMR (MeOD): 7.22-6.76 (m, 6H), 5.26-5.18 (m, 1H), 4.94-4.83 (m, 1H), 4.18-4.10 (m, 2H), 3.98-3.88 (m, 2H), 3.83 (s, 3H), 3.40-3.20 (m, 2H), 3.15-3.02 (m, 2H).

Example 179: 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-indan-1-one oxime

Step A: Preparation of 3-[5-chloro-2-(6-fluoro-1-oxo-indan-2-yloxy)-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester

The mixture of 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (0.5 mmol), 1-bromo-indan-2-one (0.5 mmol), and K₂CO₃ (1 mmol) in actetonitrile (3 mL) was heated at 100° C. in a microwave reactor for 1 h. The mixture was cooled down and separated through PTLC providing the title compound (150 mg).

Step B: Preparation of 3-[5-Chloro-2-(1-hydroxyimino-indan-2-yloxy)-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester

The title compound of Step A was dissolved into MeOH (2 mL), then NH₂OH.HCl (1 mmol) and K₂CO₃ (2 mmol) were added. The mixture was heated at 100° C. using a microwave reactor for 1 h. The mixture was cooled to rt and purified by PTLC providing the title compound (120 mg).

Step C: Preparation of 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-indan-1-one oxime

The title compound from Step B was dissolved in CH₂Cl₂ (20 mL), and CF₃COOH (3 mL) was added. The mixture was stirred at 25° C. for 4 h. After concentration and purification via PTLC, the title compound was obtained (91 mg). MS (ESI): mass calcd. for C₁₈H₁₇ClN₂O₃, 344.1; m/z found, 345.0 [M+H]⁺. ¹H NMR (MeOD): 8.40 (d, J=8.0 Hz, 1H), 7.50-6.80 (m, 6H), 5.48-5.46 (m, 1H), 5.18-5.10 (m, 1H), 4.45-4.32 (m, 2H), 4.18-4.08 (m, 2H), 3.62-3.52 (m, 1H), 3.16-3.08 (m, 1H).

Example 180-183 were prepared by the procedure of example 179 using the appropriate α-bromo-ketone and NH₂OH or NH₂OCH₃.

Example 180: 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-indan-1-one O-methyl-oxime

MS (ESI): mass calcd. for C₁₉H₁₉ClN₂O₃, 358.1; m/z found, 359.0 [M+H]⁺. ¹H NMR (MeOD): 8.70 (d, J=8.0 Hz, 1H), 7.60-6.90 (m, 6H), 6.03-5.98 (m, 1H), 5.15-5.05 (m, 1H), 4.56-4.43 (m, 2H), 4.22-1.18 (m, 2H), 3.93 (s, 3H), 3.76-3.64 (m, 1H), 3.24-3.16 (m, 1H).

Example 181: 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-1-phenyl-ethanone oxime

MS (ESI): mass calcd. for C₁₇H₁₇ClN₂O₃, 332.1; m/z found, 333.0 [M+H]⁺. ¹H NMR (MeOD): 8.12-6.80 (m, 8H), 5.56-5.30 (m, 2H), 5.25-4.80 (m, 1H), 4.60-3.98 (m, 4H).

Example 182: 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-1-phenyl-ethanone O-methyl-oxime

MS (ESI): mass calcd. for C₁₈H₁₉ClN₂O₃, 346.1; m/z found, 347.0 [M+H]⁺. ¹H NMR (MeOD): 8.18-6.80 (m, 8H), 5.56-5.33 (m, 2H), 5.32-4.80 (m, 1H), 4.60-3.98 (m, 7H).

Example 183: 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-1-(4-chloro-phenyl)-ethanone

¹H NMR (CDCl₃): 7.97 (d, J=8.6 Hz, 2H), 7.48 (d, J=8.6 Hz, 2H), 6.85 (dd, J=8.6, 2.3 Hz, 1H), 6.78 (d, J=8.6 Hz, 1H), 6.59 (d, J=8.6 Hz, 1H), 5.25 (s, 2H), 5.00-4.97 (m, 1H), 3.98-3.80 (m, 4H).

Example 184: 3-[5-Chloro-2-(2,2-difluoro-2-phenyl-ethoxy)-phenoxy]-azetidine

The mixture of 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (0.5 mmol), (2-bromo-1,1-difluoro-ethyl)-benzene (1 mmol), and K₂CO₃ (1 mmol) in acetonitrile (3 mL) was heated at 180° C. in a microwave reactor for 1 h. The mixture was cooled to rt and purified via PTLC providing 3-[5-chloro-2-(2,2-difluoro-2-phenyl-ethoxy)-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester (90 mg). To this compound was added CH₂Cl₂ (20 mL) and CF₃COOH (3 mL). The mixture was stirred at rt for 4 h and concentrated to give the title compound (50 mg). MS (ESI): mass calcd. for C₁₇H₁₆ClF₂NO₂, 339.1; m/z found, 340.0 [M+H]⁺. ¹H NMR (MeOD): 7.66-7.46 (m, 5H), 7.02-6.83 (m, 3H), 5.05-4.95 (m, 1H), 4.50 (t, J=12.7 Hz, 2H), 4.30-4.20 (m, 2H), 4.10-3.98 (m, 2H).

Example 185: 3-[5-Chloro-2-[2-(3-chloro-phenyl)-ethoxy]-phenoxy]-azetidine

Step A. Preparation of Methanesulfonic acid 2-(3-chloro-phenyl)-ethyl ester

To a solution of 2-(3-chloro-phenyl)-ethanol (566 mg, 3.6 mmol) in CH₂Cl₂ (10 mL) was added methanesulfonyl chloride (310 μL, 4.0 mmol). After 5 min, Et₃N (756 μL, 5.4 mmol) was added and the reaction was allowed to stir for 18 h. The reaction was then diluted with H₂O. The organic layer was separated and washed with H₂O, brine, then dried and concentrated to give a yellow oil (770 mg, 91%). ¹H NMR (CDCl₃): 7.27-7.23 (m, 3H), 7.14-7.11 (m, 1H), 4.41 (t, J=6.8 Hz, 2H), 3.04 (t, J=6.8 Hz, 2H), 2.90 (s, 3H).

Step B. Preparation of 3-[5-Chloro-2-[2-(3-chloro-phenyl)-ethoxy]-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester

To a solution of 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (60 mg, 0.20 mmol) in DMF (2 mL) was added NaH (10 mg, 0.24 mmol). After 5 min, the title compound of Step A (56 mg, 0.24 mmol) was added and the resulting mixture was heated at 65° C. for 18 h. The reaction was diluted with H₂O and extracted EtOAc (3×). The organics were dried and purified by RP HPLC (Agilent) to give the title compound as an oil (47 mg, 54%). MS (ESI): mass calcd. for C₂₂H₂₅Cl₂NO₄, 438.3; m/z found, 382.0 [M−56+H]⁺. ¹H NMR (CDCl₃): 7.34-7.32 (m, 1H), 7.25-7.22 (m, 2H), 7.19-7.16 (m, 1H), 6.90 (dd, J=8.8, 2.0 Hz, 1H), 6.78 (d, J=8.8 Hz, 1H), 6.54 (d, J=2.4 Hz, 1H), 4.85-4.79 (m, 1H), 4.30-4.25 (m, 2H), 4.16 (t, J=6.7 Hz, 2H), 4.07-4.03 (m, 2H), 3.10 (t, J=6.7 Hz, 2H), 1.46 (s, 9H).

Step C: Preparation of 3-[5-Chloro-2-[2-(3-chloro-phenyl)-ethoxy]-phenoxy]-azetidine

Prepared from title compound of Step B using general procedure 1. MS (ESI): mass calcd. for C₁₇H₁₇Cl₂NO₂, 338.2; m/z found, 338.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.35-7.34 (m, 1H), 7.25-7.21 (m, 3H), 7.18-7.16 (m, 1H), 6.88-6.85 (m, 1H), 6.77 (d, J=8.8 Hz, 1H), 6.57 (d, J=2.4 Hz, 1H), 4.98-4.91 (m, 1H), 4.17 (t, J=6.8 Hz, 2H), 3.96-3.85 (m, 4H), 3.10 (t, J=6.7 Hz, 2H).

The compounds in Examples 186-195 were synthesized according to Example 185 using the appropriately substituted mesylates as prepared in Example 185 Step A.

Example 186: 3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₈ClNO₂, 303.8; m/z found, 304.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.39-7.19 (m, 7H), 6.93-6.73 (m, 2H), 6.58 (d, J=2.4 Hz, 1H), 4.94 (s, 1H), 4.18 (t, J=7.3 Hz, 2H), 3.91 (s, 3H), 3.14 (t, J=7.3 Hz, 2H).

Example 187: 3-[5-Chloro-2-(2-fluoro-2-phenyl-ethoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₇ClFNO₂, 321.8; m/z found, 322.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.42 (s, 5H), 6.87-6.61 (m, 2H), 6.62 (d, J=2.2 Hz, 1H), 5.85 (dd, J=48.0, 8.0 Hz, 1H), 5.02 (bs, 1H), 4.40-4.08 (m, 7H).

Example 188: 3-[5-Chloro-2-[1-(4-chloro-phenyl)-cyclobutylmethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₂₀H₂₁Cl₂NO₂, 378.3; m/z found, 378.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.34-7.27 (m, 5H), 7.21-7.20 (m, 1H), 7.19-7.18 (m 1H), 6.81 (s, 1H), 6.70 (d, J=8.6, 1H), 6.54 (d, J=2.4 Hz, 1H), 4.97-4.87 (m, 1H), 4.01 (s, 2H), 3.94-3.90 (m, 2H), 3.82-3.78 (m, 2H), 2.42 (t, J=7.7 Hz, 4H).

Example 189: 3-[5-Chloro-2-[1-(3-chloro-phenyl)-cyclobutylmethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₂₀H₂₁Cl₂NO₂, 378.3; m/z found, 378.0. ¹H NMR (CDCl₃): 7.28-7.22 (m, 5H), 7.19-7.16 (m, 1H), 7.13-7.10 (m, 1H), 6.82 (dd, J=8.6, 2.4 Hz, 1H), 6.70 (d, J=8.6 Hz, 1H), 6.54 (d, J=2.4, 1H), 4.92 (m, 1H), 4.03 (s, 2H), 3.94-3.76 (m, 3H), 2.42 (d, J=8.8 Hz, 3H), 2.17 (s, 2H).

Example 190: 3-[5-Chloro-2-[2-(3-methoxy-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₂₀ClNO₃, 333.8; m/z found, 334.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.24-7.22 (m, 2H), 6.90-6.86 (m, 3H), 6.81-6.77 (m, 2H), 6.60 (d, J=2.4, 1H), 5.00-4.87 (m, 1H), 4.18 (t, J=7.2, 2H), 4.03-3.94 (m, 2H), 3.90-3.86 (m, 2H), 3.80 (s, 3H), 3.11 (t, J=7.1 Hz, 2H).

Example 191: 3-[5-Chloro-2-[2-(3-fluoro-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₇ClFNO₂, 321.8; m/z found, 322.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.30-7.24 (m, 2H), 7.09-7.05 (m, 2H), 6.96-6.91 (m, 1H), 6.88-6.85 (m, 1H), 6.77 (d, J=8.8 Hz, 1H), 6.57 (d, J=2.4, 1H), 4.95 (s, 1H), 4.18 (t, J=6.8 Hz, 2H), 3.95-3.84 (m, 4H), 3.12 (t, J=6.8 Hz, 2H).

Example 192: 3-[5-Chloro-2-[2-(4-chloro-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₇Cl₂NO₂, 338.2; m/z found, 338.0. ¹H NMR (CDCl₃): 7.34-7.17 (m, 5H), 6.89 (dd, J=8.6, 2.4 Hz, 1H), 6.77 (d, J=8.7 Hz, 1H), 6.60 (d, J=2.4 Hz, 1H), 4.95 (t, J=6.2 Hz, 1H), 4.16-4.13 (m, 2H), 4.04-3.99 (m, 2H), 3.93-3.89 (m, 2H), 3.09 (t, J=6.9 Hz, 2H).

Example 193: 3-[5-Chloro-2-[2-(4-fluoro-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₇H₁₇ClFNO₂, 321.8; m/z found, 322.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.32-7.20 (m, 4H), 7.00 (t, J=8.7 Hz, 1H), 6.87-6.85 (m, 1H), 6.77 (d, J=8.8 Hz, 1H), 6.57 (d, J=2.4 Hz, 1H), 5.00-4.87 (m, 1H), 4.15 (t, J=7.0 Hz, 2H), 3.94-3.90 (m, 2H), 3.85-3.81 (m, 2H), 3.10 (t, J=7.0 Hz, 2H).

Example 194: 3-[5-Chloro-2-[2-(4-methoxy-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₂₀ClNO₃, 333.8; m/z found, 334.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.22-7.20 (m, 2H), 6.93-6.85 (m, 3H), 6.77 (d, J=8.4 Hz, 1H), 6.58 (d, J=2.4 Hz, 1H), 4.98-4.91 (m, 1H), 4.13 (t, J=7.3 Hz, 2H), 3.96-3.92 (m, 2H), 3.89-3.85 (m, 2H), 3.79 (s, 3H), 3.07 (t, J=7.3 Hz, 2H).

Example 195: 3-(5-Bromo-2-phenethyloxy-phenoxy)-azetidine

Prepared according to Example 185 using 3-(5-Bromo-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester. MS (ESI): mass calcd. for C₁₇H₁₈BrNO₂, 348.2; m/z found, 348.0. ¹H NMR (CDCl₃): 7.39-7.20 (m, 6H), 7.05 (dd, J=8.6, 2.3 Hz, 1H), 6.76 (dd, J=6.8, 5.5 Hz, 2H), 4.99-4.87 (m, 1H), 4.18 (t, J=7.2 Hz, 2H), 4.03-3.98 (m, 2H), 3.95-3.91 (m, 2H), 3.13 (t, J=7.2 Hz, 2H).

Example 196: 3-(Azetidin-3-yloxy)-2-benzyloxy-5-chloro-pyridine

Step A: Preparation of 2-benzyloxy-5-chloro-3-fluoro-pyridine

To 60% NaH in mineral oil (1.0 g, 25.0 mmol) in THF (25 mL) was added benzyl alcohol (2.7 g, 2.6 mL, 25.0 mmol) dropwise. After 1 h, 5-chloro-2,3-difluoro-pyridine (3.73 g, 25.0 mmol) was added in THF (5 mL). After an additional 18 h, H₂O was added and the mixture extracted with EtOAc (2×). The combined organics were washed with brine and dried. Silica gel chromatography (1-15% EtOAc in hexanes) gave 4.02 g (67% yield) of the title compound as a clear oil. ¹H NMR (CDCl₃): 7.91 (d, J=2.2 Hz, 1H), 7.48-7.46 (m, 2H), 7.39-7.32 (m, 4H), 5.44 (s, 2H).

Step B: Preparation of 3-(2-Benzyloxy-5-chloro-pyridin-3-yloxy)-azetidine-1-carboxylic acid tert-butyl ester

To 3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (0.35 g, 2.0 mmol) in NMP (3 mL) was added 60% NaH in mineral oil (0.08 g, 2.0 mmol). After 20 min at rt, the reaction was heated to 50° C. for 20 min, cooled to rt and the title compound from step A (0.40 g, 1.7 mmol) in NMP (1 mL) was added. The reaction was then heated in a microwave reactor at 145° C. for 1 h, cooled to rt, poured into H₂O and extracted with EtOAc (2×). The combined organics were washed with brine and dried.

Silica gel chromatography (2-15% EtOAc in hexanes) gave 0.34 g (51% yield) of the title compound as a white solid. ¹H NMR (CDCl₃): 7.74 (d, J=2.1 Hz, 1H), 7.46 (d, J=7.0 Hz, 2H), 7.39-7.30 (m, 3H), 6.77 (d, J=2.1 Hz, 1H), 5.42 (s, 2H), 4.87-4.82 (m, 1H), 4.26 (dd, J=10.5, 6.4 Hz, 2H), 4.05 (dd, J=10.3, 4.2 Hz, 2H), 1.44 (s, 9H).

Step C: Preparation of 3-(Azetidin-3-yloxy)-2-benzyloxy-5-chloro-pyridine

Prepared from the title compound of Step B using general procedure 1. MS (ESI): mass calcd. for C₁₅H₁₅ClN₂O₂, 290.1; m/z found, 291.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.70 (d, J=2.2 Hz, 1H), 7.46 (d, J=7.3 Hz, 2H), 7.37 (t, J=7.2 Hz, 2H), 7.33-7.29 (m, 1H), 6.77 (d, J=2.2 Hz, 1H), 5.43 (s, 2H), 4.99-4.93 (m, 1H), 3.96-3.81 (m, 4H).

Example 197: 3-(2-Benzyloxy-5-chloro-3-fluoro-phenoxy)-azetidine

Step A: Preparation of 4-Chloro-2,6-difluoro-benzaldehyde

To a −78° C. solution of 1-chloro-3,5-difluoro-benzene (5.0 g, 34 mmol) in THF (70 mL) at was added n-butyl lithium (1.6M in hexane, 19 mL). After 50 min, DMF (5.2 mL, 67 mmol) was added and the reaction was allowed to warm to rt over 18 h. After the addition of 0.5M HCl (150 mL) and ether (150 mL), the aqueous layer was extracted with Et₂O (3×). The combined organic extracts were dried and concentrated to provide a yellow solid. The crude material was dissolved in warm hexanes and a small amount of white solid formed upon cooling. This white solid was filtered off and discarded. The filtrate was concentrated to provide the title compound as a light yellow solid (2.5 g, 41%). ¹H NMR (CDCl₃): 10.3 (s, 1H), 7.06 (d, J=8.1 Hz, 2H).

Step B: Preparation of 3-(5-Chloro-3-fluoro-2-formyl-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester

To a solution of the title compound of Step A (270 mg, 1.5 mmol) and 3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (270 mg, 1.5 mmol) in dry DMF (10 mL) at 0° C. was added NaH (60% in mineral oil, 22 mg, 1.5 mmol). After 18 h, H₂O and EtOAc were added and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried and concentrated. The crude residue was purified by RP HPLC to provide the title compound (75 mg, 15%). MS (ESI): mass calcd. for C₁₅H₁₇ClFNO₄, 329.1; m/z found, 274.0 [M+H−56]⁺. ¹H NMR (CDCl₃): 10.4 (s, 1H), 6.84 (dd, J=10.0, 1.6 Hz, 1H), 6.39 (dd, J=1.4, 1.3 Hz, 1H), 5.00-4.92 (m, 1H), 4.38 (dd, J=9.9, 6.3 Hz, 2H), 4.08 (dd, J=10.7, 4.0 Hz, 2H), 1.46 (s, 9H).

Step C: Preparation of 3-(5-Chloro-3-fluoro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester

To a solution of the title compound of Step B (650 mg, 2.0 mmol) in CH₂Cl₂ (100 mL) was added 77% m-CPBA (510 mg, 3.0 mmol). After stirring for 72 h, the starting aldehyde remained as determined by analytical HPLC analysis. Thus an additional portion of m-CPBA (790 mg, 4.6 mmol) was added. After 18 h, analytical HPLC analysis indicated that the reaction was complete. A solution of 10% aqueous sodium bisulfite (100 mL) was added to the reaction mixture. After an additional 18 h, CH₂Cl₂ was added and the aqueous portion extracted three times with CH₂Cl₂. The combined organic extracts were washed with saturated NaHCO₃ (2×) and concentrated. The residue was then treated with MeOH (500 mL) and 1N NaOH (250 mL). The solution immediately turned dark brown. After 2 h, the MeOH was removed by rotary evaporation and 1M KHSO₄ was added to the residue until the pH of the solution reached pH=4. The reaction mixture was then extracted with EtOAc (3×). The combined organic layers were washed with brine and dried. The residue was purified by RP HPLC to provide the desired phenol (290 mg, 46%). ¹H NMR (CDCl₃): 6.74 (dd, J=10.1, 2.3 Hz, 1H), 6.30 (dd, J=2.0, 2.1 Hz, 1H), 4.87-4.80 (m, 1H), 4.26 (dd, J=9.9, 6.4 Hz, 2H), 4.00 (dd, J=9.9, 3.8 Hz, 2H), 3.29-3.13 (m, 1H), 1.40 (s, 9H).

Step D: Preparation of 3-(2-Benzyloxy-5-chloro-3-fluoro-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester

Prepared from the title compound of Step C using according to Example 1 Step D. MS (ESI): mass calcd. for C₂₁H₂₃ClFNO₄, 407.1; m/z found, 430.0 [M+Na]⁺. ¹H NMR (CDCl₃): 7.46-7.29 (m, 5H), 6.79 (dd, J=9.9, 2.4 Hz, 1H), 6.29 (dd, J=2.1, 2.1 Hz, 1H), 5.06 (s, 2H), 4.82-4.72 (m, 1H), 4.25 (ddd, J=9.7, 6.4, 1.0 Hz, 2H), 3.92 (dd, J=9.8, 3.9 Hz, 2H), 1.46 (s, 9H).

Step E: Preparation of 3-(2-Benzyloxy-5-chloro-3-fluoro-phenoxy)-azetidine

Prepared from the title compound of Step D using general procedure 1. MS (ESI): mass calcd. for C₁₆H₁₅ClFNO₂, 307.1; m/z found, 308.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.47-7.41 (m, 2H), 7.37-7.30 (m, 3H), 6.76 (dd, J=9.9, 2.4 Hz, 1H), 6.34 (dd, J=2.1, 2.1 Hz, 1H), 5.06 (s, 2H), 4.97-4.86 (m, 1H), 4.05-3.63 (m, 4H), 2.27-2.00 (m, 1H).

Example 198: 3-[5-Chloro-3-fluoro-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-azetidine

Prepared according to Example 199 using 2-bromomethyl-5-trifluoromethyl-furan. MS (ESI): mass calcd. for C₁₅H₁₂ClF₄NO₃, 365.0; m/z found, 367.0 [M+H]⁺. ¹H NMR (CDC₃): 6.78-6.72 (m, 2H), 6.42 (d, J=3.3 Hz, 1H), 6.36 (dd, J=2.1, 2.1 Hz, 1H), 5.04 (s, 2H), 4.98-4.85 (m, 1H), 4.05-3.69 (m, 4H), 2.20-1.99 (m, 1H).

Example 199: 3-[5-Trifluoromethyl-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-azetidine

Prepared according to Example 1 using 3-(2-hydroxy-5-trifluoromethyl-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester and 2-bromomethyl-5-trifluoromethyl-furan. MS (ESI): mass calcd. for C₁₆H₁₃F₆N₃O₃, 381.1; m/z found, 382.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.21 (dd, J=8.4, 1.2 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.83 (d, J=2.0 Hz, 1H), 6.79-6.78 (m, 1H), 6.51 (d, J=3.1 Hz, 1H), 5.13 (s, 2H), 5.05-4.99 (m, 1H), 3.94-3.87 (m, 4H).

Example 200: 3-[5-Trifluoromethyl-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine

Prepared according to Example 101 using 3-(2-hydroxy-5-trifluoromethyl-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester. MS (ESI): mass calcd. for C₁₉H₁₇F₆NO₂, 405.1; m/z found, 406.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.70 (s, 1H), 7.56 (t, J=7.6 Hz, 2H), 7.47 (t, J=7.7 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 6.83-6.80 (m, 2H), 5.41 (q, J=6.4 Hz, 1H), 5.07 (br s, 1H), 4.33-3.64 (m, 4H), 1.70 (d, J=6.5 Hz, 3H).

Example 201: 3-[2-(1-Phenyl-ethoxy)-5-trifluoromethyl-phenoxy]-azetidine hydrochloride

Prepared according to Example 1 using 3-(2-hydroxy-5-trifluoromethyl-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester and benzyl bromide. MS (ESI): mass calcd. for C₁₇H₁₆F₃NO₂, 323.1; m/z found, 324.1 [M+H]⁺. ¹H NMR (DMSO-D₆): 9.39 (s, 2H), 7.49-7.48 (m, 2H), 7.44-7.34 (m, 2H), 7.30 (d, J=8.5 Hz, 1H), 7.13 (d, J=1.9 Hz, 1H), 5.23 (s, 2H), 5.14-5.10 (m, 1H), 4.39-4.34 (m, 2H), 4.01-3.98 (m, 2H).

Example 202: 3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-azetidine hydrochloride

Step A: Preparation of 2-(3-Chloro-benzyloxy)-5-fluoro-benzaldehyde

A mixture of 5-fluorosalicyladehyde (5.0 g, 36 mmol), 3-chloro-benzyl bromide (7.34 g, 35.7 mmol), K₂CO₃ (6.0 g, 43 mmol) in DMF (50 mL) was heated at 65° C. for 18 h. The reaction mixture was cooled to rt and diluted with a mixture of EtOAc (500 mL) and H₂O (300 mL). The organic phase was separated, washed with H₂O (3×250 mL), and dried to give the title compound (9.4 g, 99%) that was used without further purification.

Step B: Preparation of 2-(3-Chloro-benzyloxy)-5-fluoro-phenol

To the title compound from Step A (9.4 g, 36 mmol) in CH₂Cl₂ (200 mL) was added 77% m-CPBA (12.0 g, 54.0 mmol). The mixture was allowed to stir for 36 h at rt and 10 wt % NaHSO₃ (aq.) solution was added. After 48 h, the reaction mixture was washed with H₂O (2×250 mL). The organic layer was dried and treated with 1N NaOH (100 mL) and MeOH (100 mL). After 48 h, the MeOH was removed and 1N H₂SO₄ was added slowly to adjust the pH to 1.5. The resulting solution was extracted with CH₂Cl₂ (3×150 mL). The combined extracts were washed with H₂O and dried to give a red oil (8.4 g). Chromatography (SiO₂. 0-20% EtOAc/hexane) gave the title compound (5.0 g, 56%). ¹H NMR (CDCl₃) 7.50-7.16 (m, 4H), 6.87-6.57 (m, 2H), 6.50 (t, J=8.6, 3.0 Hz, 1H), 5.80 (s, 1H), 5.05-4.89 (m, 2H).

Step C: Preparation of 3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester

To the title compound of Step B (200 mg, 0.79 mmol) in DMF (5.0 mL) was added 60 wt % NaH (34.3 mg, 0.86 mmol). The mixture was heated to 50° C. for 1 h then cooled to rt and 3-methanesulfonyloxy-azetidine-1-carboxylic acid tert-butyl ester (Example 90 Step A, 229 mg, 0.91 mmol) in DMF was added. This mixture was heated to 80° C. for 18 h, cooled to rt and treated with EtOAc (50 mL) and H₂O (100 mL). The organic layer was separated, washed with H₂O (2×50 mL) and dried to give a solid (400 mg). This solid was purified on RP HPLC to yield the title compound (90 mg, 28%). ¹H NMR (CDCl₃) 7.44 (s, 1H), 7.36-7.23 (m, 3H), 6.86 (dd, J=8.9, 5.4 Hz, 1H), 6.60 (dd, J=8.0, 2.9 Hz, 1H), 6.33 (dd, J=9.6, 2.9 Hz, 1H), 5.03 (s, 2H), 4.90-4.80 (m, 1H), 4.33-4.22 (m, 2H), 4.07-4.02 (m, 2H), 1.54-1.28 (m, 9H).

Step D: Preparation of 3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-azetidine hydrochloride

The title compound from step C (85 mg) was dissolved in MeOH (5 mL) and 4M HCl in dioxane (3 mL) was added. The mixture was stirred at rt for 18 h. The reaction was concentrated and dried under vacuum to yield the title compound (75 mg). MS (ESI): mass calcd. for C₁₆H₁₅ClFNO₂, 307.8; m/z found, 310.2 [M+H]⁺. ¹H NMR (MeOD): 7.46 (s, 1H), 7.37-7.28 (m, 3H), 7.04 (dd, J=9.0 Hz, 5.3, 1H), 6.75-6.61 (m, 2H), 5.09-5.00 (m, 3H), 4.42 (dd, J=12.7, 6.6 Hz, 2H), 4.14 (dd, J=12.7, 4.9 Hz, 2H).

Example 203: 3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-1-methyl-azetidine

Prepared according to general procedure 5 using the title compound from Example 202. MS (ESI): mass calcd. for C₁₇H₁₇ClFNO₂, 321.8; m/z found, 322.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.47-7.39 (m, 1H), 7.31-7.25 (m, 3H), 6.81 (dd, J=8.9, 5.5 Hz, 1H), 6.56-6.52 (m, 1H), 6.38 (dd, J=9.9, 2.9 Hz, 1H), 5.02 (s, 2H), 4.72-4.67 (m, 1H), 3.87-3.78 (m, 2H), 3.17-3.08 (m, 2H), 2.40 (s, 3H).

Example 204: 3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-1-isopropyl-azetidine

Prepared according to general procedure 3 or 4 using the title compound from Example 202. MS (ESI): mass calcd. for C₁₉H₂₁ClFNO₂, 349.8; m/z found, 350.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.44 (s, 1H), 7.29-7.26 (m, 3H), 6.81 (dd, J=8.9, 5.5 Hz, 1H), 6.54-6.52 (m, 1H), 6.41 (dd, J=9.9, 2.9, 1H), 5.01 (s, 2H), 4.73-4.68 (m, 1H), 3.85-3.77 (m, 2H), 3.11-3.04 (m, 2H), 2.43-2.36 (m, 1H), 0.95 (d, J=6.2 Hz, 6H).

Example 205: 3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-1-cyclobutyl-azetidine

Prepared according to general procedure 3 or 4 using the title compound from Example 202. MS (ESI): mass calcd. for C₂₀H₂₁ClFNO₂, 361.8; m/z found, 362.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.44 (s, 1H), 7.32-7.22 (m, 3H), 6.82 (dd, J=8.9, 5.5 Hz, 1H), 6.57-6.53 (m, 1H), 6.41 (dd, J=9.8, 2.9 Hz, 1H), 5.02 (s, 2H), 4.77-4.72 (m, 1H), 3.77-3.69 (m, 2H), 3.23-3.12 (m, 3H), 2.01-1.95 (m, 2H), 1.87-1.62 (m, 4H).

Example 206: 3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-1-propyl-azetidine

Prepared according to general procedure 3 or 4 using the title compound from Example 202. MS (ESI): mass calcd. for C₁₉H₂₁ClFNO₂, 349.8; m/z found, 350.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.46 (s, 1H), 7.30 (m, 3H), 6.83 (dd, J=8.9, 5.5 Hz, 1H), 6.59-6.51 (m, 1H), 6.42 (dd, J=9.9, 2.9 Hz, 1H), 5.04 (s, 2H), 4.78-4.73 (m, 1H), 3.8-3.80 (m, 2H), 3.13-3.05 (m, 2H), 2.52-2.44 (m, 2H), 1.45-1.34 (m, 2H), 0.91 (t, J=7.4 Hz, 3H).

Example 207: 3-[2-(3-Chloro-benzyloxy)-5-fluoro-phenoxy]-1-ethyl-azetidine

Prepared according to general procedure 3 or 4 using the title compound from Example 202. MS (ESI) mass calcd. for C₁₈H₁₉ClFNO₂, 335.8; m/z found, 338.2 [M+H]⁺. ¹H NMR (CDCl₃) 7.47 (s, 1H), 7.32-7.28 (m, 3H), 6.84 (dd, J=8.9, 5.5 Hz, 1H), 6.59-6.55 (m, 1H), 6.43 (dd, J=9.8, 2.9 Hz, 1H), 5.04 (s, 2H), 4.79-4.74 (m, 1H), 3.87-3.80 (m, 2H), 3.15-3.06 (m, 2H), 2.59-2.54 (m, 2H), 1.01 (dd, J=8.8, 5.6 Hz, 3H).

Example 208: 3-[5-Fluoro-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-azetidine

Prepared according top Example 202 using 2-bromomethyl-5-trifluoromethyl-furan. MS (ESI): mass calcd. for C₁₅H₁₃F₄NO₃, 331.26; m/z found, 332.2 [M+H]⁺. ¹H NMR (CDCl₃): 6.91 (dd, J=8.9, 5.5 Hz, 1H), 6.77 (d, J=2.3, 1H), 6.66-6.53 (m, 1H), 6.49-6.29 (m, 2H), 5.04 (s, 2H), 5.00-4.92 (m, 1H), 3.98-3.94 (m, 4H), 2.44 (s br, 1H).

Example 209: 3-[5-Fluoro-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-1-isopropyl-azetidine

Prepared according to general procedure 3 or 4 using the title compound from Example 208. MS (ESI): mass calcd. for C₁₈H₁₉F₄NO₃, 373.3; m/z found, 374.1 [M+H]⁺. ¹H NMR (CDCl₃): 6.89 (dd, J=8.9, 5.5 Hz, 1H), 6.77-6.75 (m, 1H), 6.63-6.51 (m, 1H), 6.44-6.41 (m, 2H), 5.01 (s, 2H), 4.78-4.58 (m, 1H), 3.83 (dd, J=8.8, 6.0 Hz, 2H), 3.09 (dd, J=8.8, 6.0 Hz, 2H), 2.47-2.31 (m, 1H), 0.97 (d, J=6.2 Hz, 6H).

Example 210: 3-[2-(3-Chloro-benzyloxy)-5-thiophen-3-yl-phenoxy]-azetidine

3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester (188 mg, 0.4 mmol), 3-thiophene boronic acid (53 mg, 0.41 mmol), Q-Phos (23 mg, 0.032 mmol), Pd(dba)₂ (9.2 mg, 0.016 mmol) and K₃PO₄ (255 mg, 1.2 mmol) were taken into toluene (3 mL) and heated at 80° C. After the reaction was complete it was cooled to rt, diluted with CH₂Cl₂ (20 mL), filtered, washed with H₂O (2×25 mL) and concentrated to give 3-[2-(3-chloro-benzyloxy)-5-thiophen-3-yl-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester. To this compound was added MeOH (10 mL) followed by 4M HCl in dioxane (4 mL). After 4 h the reaction was concentrated and purified on RP HPLC (basic) to yield the title compound (12 mg). MS (ESI): mass calcd. for C₂₀H₁₈ClNO₂S, 371.9; m/z found, 372.2 [M+H]⁺. ¹H NMR (CDCl₃): 10.30-9.57 (m, 1H), 7.43 (s, 1H), 7.40-7.28 (m, 6H), 7.24 (dd, J=8.4, 2.1 Hz, 1H), 7.01 (d, J=2.1 Hz, 1H), 6.96 (d, J=8.5 Hz, 1H), 5.24-4.99 (m, 3H), 4.40-4.11 (m, 4H).

Example 211: 3-(Azetidin-3-yloxy)-4-(3-chloro-benzyloxy)-N,N-dimethyl-benzamide

A suspension of 3-[5-bromo-2-(3-chloro-benzyloxy)-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester (94 mg, 0.2 mmol), Na₂CO₃ (53 mg, 0.5 mmol), 40% Me₂NH in H₂O (0.17 mmol), Hermann's catalyst (8 mg, 0.008 mmol) and Mo(CO)₆ (22 mg, 0.083 mmol) in H₂O (2 mL) was heated to 170° C. in a microwave reactor for 10 min. The reaction was cooled rt, and saturated NaHCO₃ (aq.) was added. This solution was extracted with CH₂Cl₂ (3×). The combined organic layers were concentrated to give a solid (30 mg) that was dissolved in MeOH (2 mL) and treated with 4M HCl in dioxane (1 mL). After 3 h, the mixture was concentrated to give a residue that was purified on RP HPLC providing the title compound (5 mg). MS (ESI): mass calcd. for C₁₉H₂₁ClN₂O₃, 360.8; m/z found, 361.5 [M+H]⁺. ¹H NMR (CDCl₃): 7.45 (s, 1H), 7.29-7.27 (m, 3H), 6.96 (dd, J=8.2, 1.9 Hz, 1H), 6.87 (d, J=8.3 Hz, 1H), 6.72 (d, J=1.9 Hz, 1H), 5.11 (s, 2H), 5.05-4.95 (m, 1H), 3.92-3.85 (m, 4H), 3.00 (s br, 6H).

Example 212: 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-3-methyl-azetidine

Step A: Preparation of 1-benzhydryl-3-methyl-azetidin-3-ol

To 1-benzhydryl-azetidin-3-one (1.0 g, 4.2 mmol) in ether (100 mL) at 0° C. was added CH₃MgBr (1.5 mL, 3M in ether). The mixture was warmed to rt over 1 h and 1N NaOH (3 mL) was added. The organic layer was concentrated providing the title compound (1.1 g). MS (ESI): mass calcd. for C₁₇H₁₉NO, 253.2; m/z found, 254.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.42-7.11 (m, 10H), 4.32 (s, 1H), 3.14 (d, J=8.5 Hz, 2H), 2.96 (d, J=8.5 Hz, 2H), 1.43 (s, 3H).

Step B: Preparation of 1-benzhydryl-3-[5-bromo-2-(3-chloro-benzyloxy)-phenoxy]-3-methyl-azetidine

The mixture of the title compound from Step A (0.5 mmol), 5-bromo-2-(3-chloro-benzyloxy)-phenol (0.5 mmol), and cyanomethylenetri-n-butylphosphorane (0.5 mmol) in toluene (3 mL) was heated at 150° C. in a microwave reactor for 1 h. The mixture was cooled to rt and purified via PTLC providing the title compound (120 mg). MS (ESI): mass calcd. for C₃₀H₂₇BrClNO₂, 547.1; m/z found, 548.0 [M+H]⁺.

Step C: Preparation of 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-3-methyl-azetidine

The title compound from Step B (60 mg) was dissolved in DCE (10 mL) and chloroethylformate (0.2 mmol) was added. The mixture was heated at 80-100° C. for 1 h and concentrated. The residue was dissolved in MeOH (3 mL) and heated at 150° C. in a microwave reactor for another 1 h. The mixture was cooled to rt and purified via PTLC providing the title compound (30 mg). MS (ESI): mass calcd. for C₁₇H₁₇BrClNO₂, 381.0; m/z found, 382.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.43-7.23 (m, 4H), 7.12-7.06 (m, 1H), 6.86-6.78 (m, 2H), 5.12 (s, 2H), 4.24-4.16 (m, 2H), 3.78-3.67 (m, 2H), 1.67 (s, 3H).

Example 213: 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-3-ethyl-azetidine

Prepared according to Example 212 using the ethylmagnesium bromide in Step A. MS (ESI): mass calcd. for C₁₈H₁₉BrClNO₂, 395.0; m/z found, 396.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.41-7.25 (m, 4H), 7.15-7.05 (m, 1H), 6.84-6.73 (m, 2H), 5.13 (s, 2H), 4.26-4.19 (m, 2H), 3.85-3.74 (m, 2H), 2.19-2.00 (m, 2H), 1.00-0.90 (m, 3H).

Example 214: 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-3-isopropyl-azetidine

Prepared according to Example 212 using the isopropylmagnesium bromide in Step A. MS (ESI): mass calcd. for C₁₉H₂₁BrClNO₂, 409.0; m/z found, 409.9 [M+H]⁺. ¹H NMR (CDCl₃): 7.43-7.23 (m, 4H), 7.14-6.78 (m, 3H), 5.13 (s, 2H), 3.98-3.85 (m, 2H), 3.48-3.33 (m, 2H), 1.45-1.36 (m, 1H), 0.63-0.50 (m, 6H).

Example 215: 3-(5-Bromo-2-phenethyloxy-phenoxy)-3-methyl-azetidine

Step A: Preparation of (4-Bromo-2-fluoro-benzylidene)-tert-butyl-amine

A mixture of 4-bromo-2-fluorobenzaldehyde (10 g, 47 mmol), tert-butyl amine (6.1 mL, 57 mmol) and 4 Å powder molecular sieves (8.0 g) in 160 mL CH₂Cl₂ (160 mL) was stirred at rt for 18 h. The reaction mixture was filtered through a pad of celite and concentrated to give the title compound (9.9 g, 78%). MS (ESI): mass calcd. for C₁₁H₁₃BrFNO, 258.1; m/z found, 260.0 [M+H]⁺. ¹H NMR (CDCl₃): 10.32 (s, 1H), 8.48 (s, 1H), 7.89 (t, J=8.1 Hz, 1H), 7.50-7.20 (m, 1H), 1.49-1.08 (m, 9H).

Step B: Preparation of 3-hydroxy-3-methyl-azetidine-1-carboxylic acid tert-butyl ester

A solution of 1-Boc-azetidin-3-one (3.5 g, 20 mmol) in 50 mL anh Et₂O was cooled to 0° C. and 3M MeMgBr in Et₂O (10 mL, 30 mmol) was added dropwise over 1 h. After 45 min, the reaction was allowed to warm to rt and stir an additional for 18 h. Then ½ sat'd NH₄Cl (aq.) was added and the mixture extracted with EtOAc (2×). The combined organic layers were dried and the resulting semisolid was purified by RP HPLC (Agilent) to give the title compound as a white solid (3.2 g, 84%). ¹H NMR (CDCl₃): 3.84 (q, J=9.2 Hz, 4H), 1.97 (bs, 1H), 1.52 (s, 3H), 1.44 (m, 9H).

Step C: Preparation of 3-(5-Bromo-2-formyl-phenoxy)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester

To a solution of the title compound from Step B (400 mg, 2.2 mmol) in DMSO (8 mL) was added 60% NaH (120 mg, 3.0 mmol). After 30 min, the title compound from Step A was added and the resulting mixture was heated at 125° C. for 1 h in a microwave reactor. An additional quantity of the title compound from Step B (100 mg) and 60% NaH (32 mg) were added to the reaction. Heating was then resumed at 125° C. for another 1 h in a microwave reactor. The reaction was diluted with H₂O and extracted with EtOAc (3×) followed by methanolic EtOAc (2×). The organics were dried, then THF (5 mL), H₂O (5 mL) and AcOH (3 mL) were added. After 18 h at rt, the reaction was diluted with H₂O and extracted with CH₂Cl₂. The organics were dried and purified by PTLC to give the title compound as an off white solid (247 mg, 31%). ¹H NMR (CDCl₃): 10.36 (s, 1H), 7.74 (d, J=8.3 Hz, 1H), 7.22-7.20 (m, 1H), 6.68 (d, J=1.6 Hz, 1H), 4.25 (d, J=9.2 Hz, 2H), 4.03 (d, J=9.8 Hz, 2H), 1.55 (s, 3H), 1.46 (m, 9H).

Step D: Preparation of 3-(5-Bromo-2-hydroxy-phenoxy)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester

Prepared according to Example 1 Step C using the title compound from Step C. Purification was accomplished by PTLC to give the title compound as a peach solid (152 mg, 64%). ¹H NMR (CDCl₃): 7.02 (dd, J=8.5, 2.2 Hz, 1H), 6.84 (d, J=8.5 Hz, 1H), 6.63 (d, J=2.2 Hz, 1H), 4.22 (d, J=9.2 Hz, 2H), 3.98 (d, J=9.5 Hz, 2H), 3.49 (s, 1H), 1.69 (s, 3H), 1.46 (s, 9H).

Step E. Preparation of 3-(5-Bromo-2-phenethyloxy-phenoxy)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester

A mixture of 3-(5-bromo-2-hydroxy-phenoxy)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (30 mg. 0.08 mmol), (2-bromoethyl)benzene (29 μL, 0.21 mmol), KI (42 mg, 0.25 mmol) and Cs₂CO₃ (82 mg, 0.25 mmol) in 3 mL DMF was stirred at rt for 18 h. The reaction mixture was diluted with H₂O and extracted with EtOAc (3×). The organic layers were dried and purified by RP HPLC (Agilent) to give the title compound as an oil (22 mg, 58%). MS (ESI): mass calcd. for C₂₃H₂₈BrNO₄, 462.4; m/z found, 408.0 [M−56+H]⁺. ¹H NMR (CDCl₃): 7.38-7.18 (m, 5H), 7.07 (dd, J=8.6, 2.3 Hz, 1H), 6.76-6.74 (m, 2H), 4.24-4.08 (m, 4H), 3.84 (d, J=9.7 Hz, 2H), 3.11 (t, J=7.1 Hz, 2H), 1.58 (s, 3H), 1.45 (s, 9H).

Step F: Preparation of 3-(5-Bromo-2-phenethyloxy-phenoxy)-3-methyl-azetidine

A mixture of 3-(5-bromo-2-phenethyloxy-phenoxy)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (20 mg) and TFA (1 mL) in CH₂Cl₂ (2 mL) was stirred at rt for 2 h. The reaction was concentrated in vacuo and purified by PTLC followed by additional purification using RP HPLC (Agilent) to give the title compound as an oil (12 mg, 77%). MS (ESI): mass calcd. for C₁₈H₂₀BrNO₂, 362.3; m/z found, 362.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.38-7.18 (m, 5H), 7.04 (dd, J=8.6, 2.3 Hz, 1H), 6.74 (dd, J=5.5, 3.1, 2H), 4.15 (t, J=7.2 Hz, 2H), 3.97 (d, J=8.9 Hz, 2H), 3.45 (d, J=9.2 Hz, 2H), 3.11 (t, J=7.1 Hz, 2H), 1.98 (s, 1H), 1.65 (s, 3H).

The compounds in Examples 216-217 were prepared according to Example 215 using the appropriate alkyl halide in Step E.

Example 216: 3-[5-Bromo-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₆H₁₅BrF₃NO₃, 406.2; m/z found, 407.9 [M+H]⁺. ¹H NMR (CDCl₃): 7.05 (dd, J=8.6, 2.3 Hz, 1H), 6.83 (d, J=8.8 Hz, 1H), 6.76-6.75 (m, 2H), 6.45-6.44 (m, 1H), 5.02 (s, 2H), 4.00 (d, J=9.0 Hz, 2H), 3.59-3.43 (m, 2H), 2.35 (br s, 1H), 1.67 (s, 3H).

Example 217: 3-[5-Bromo-2-(3-trifluoromethyl-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₈H₁₇BrF₃NO₂, 416.2; m/z found, 416.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.72 (bs, 1H), 7.59-7.57 (m, 2H), 7.51-7.46 (m, 2H), 7.03 (dd, J=8.6, 2.3 Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 6.74 (d, J=2.4 Hz, 1H), 5.11 (s, 2H), 4.03 (br s, 2H), 3.54 (bs, 2H), 1.71 (s, 3H).

Example 218: 3-(5-Bromo-2-phenoxy-phenoxy)-3-methyl-azetidine

Prepared according to general procedure 6 using the title compound of Example 215 Step D. MS (ESI): mass calcd. for C₁₆H₁₆BrNO₂, 334.2; m/z found, 334.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.34-7.24 (m, 2H), 7.08-7.04 (m, 2H), 6.94-6.86 (m, 3H), 6.80 (d, J=2.3, 1H), 3.88 (d, J=8.3 Hz, 2H), 3.46 (d, J=8.7 Hz, 2H), 1.85 (br s, 1H), 1.65 (s, 3H).

Example 219: (±)-trans-3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-2-methyl-azetidine

Step A. Preparation of (±)-2-bromomethyl-3-methyl-oxirane

See Shimizu et al., Organic Process & Research Development, 2005, Vol 9(3), pp. 278-287. To a stirred solution of crotyl bromide (10 g, 63 mmol) in CH₂Cl₂ (200 mL) was slowly added 77% m-CPBA (19.8 g, 88 mmol) portionwise over 45 min. After stirring at rt for 18 h, the solids were removed by filtration. The filtrate was treated with aqueous 10% aq. NaHSO₃ (150 mL) and stirred at rt for 5 h. The organic layer was separated, washed with sat'd NaHCO₃ (3×), brine (2×) and dried to give the title compound as a colorless oil (6.6 g, 70%). ¹H NMR (CDCl₃): 3.43-3.39 (m, 1H), 3.35-3.18 (m, 1H), 3.04-2.89 (m, 2H), 1.35 (d, J=5.2 Hz, 3H).

Step B. Preparation of cis and trans 1-benzhydryl-2-methyl-azetidin-3-ol

See PCT pat appl. WO 01/01988. A mixture of 2-bromomethyl-3-methyl-oxirane (3.6 g, 23.8 mmol) and aminodiphenylmethane (4.1 mL, 23.8 mmol) in 12 mL MeOH was stirred at rt for 72 h. Next, the reaction was heated at reflux for 72 h. After cooling to rt, the reaction was purified by reverse phase basic HPLC (Agilent) to give the cis and trans isomers of the title compound. Trans isomer as an oil (424 mg), ¹H NMR (CDCl₃): 7.44-7.35 (m, 4H), 7.28-7.12 (m, 7H), 4.34 (s, 1H), 3.93-3.90 (m, 1H), 3.67-3.64 (m, 1H), 3.03-2.99 (m, 1H), 2.57-2.55 (m, 1H), 0.75 (d, J=6.1, 3H). Cis isomer as an off white solid (914 mg), ¹H NMR (CDCl₃): 7.42-7.36 (m, 4H), 7.28-7.22 (m, 4H), 7.18-7.16 (m, 2H), 4.37 (s, 1H), 4.30-4.27 (m, 1H), 3.46-3.42 (m, 1H), 3.26-3.24 (m, 1H), 3.06-3.04 (m, 1H), 0.74 (d, J=6.5 Hz, 3H).

Step C. Preparation of (±)-trans-1-3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-2-methyl-azetidine

Prepared according to Example 212 Steps B-C using the trans-isomer from Step B. MS (ESI): mass calcd. for C₁₇H₁₇BrFNO₂, 365.0; m/z found, 366.1 [M+H]⁺. ¹H NMR (MeOD): 7.43-6.95 (m, 7H), 5.12 (s, 2H), 4.68-4.62 (m, 1H), 4.32-4.25 (m, 1H), 3.98-3.92 (m, 1H), 3.75-3.68 (m, 1H), 1.44 (d, J=6.7 Hz, 3H).

Example 220: cis-1-Benzyl-3-[5-bromo-2-(3-fluoro-benzyloxy)-phenoxy]-2-methyl-azetidine

Prepared from cis-(±)-1-benzyl-2-methyl-azetidin-3-ol according to Example 219. MS (ESI): mass calcd. for C₂₄H₂₃BrFNO₂, 455.1; m/z found, 456.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.39-6.94 (m, 11H), 6.78-6.69 (m, 2H), 5.08 (s, 2H), 4.78-4.72 (m, 1H), 3.76-3.62 (m, 3H), 3.54-3.48 (m, 1H), 3.34-3.26 (m, 1H), 1.20 (d, J=6.4 Hz. 3H).

Example 221: trans-1-Benzyl-3-[5-bromo-2-(3-fluoro-benzyloxy)-phenoxy]-2-methyl-azetidine

Prepared from trans-(±)-1-benzyl-2-methyl-azetidin-3-ol according to Example 219. MS (ESI): mass calcd. for C₂₄H₂₃BrFNO₂, 455.1; m/z found, 456.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.38-7.22 (m, 5H), 7.17-7.16 (m, 2H), 7.05-6.96 (m, 2H), 6.84 (d, J=2.2 Hz, 1H), 6.74 (d, J=8.6 Hz, 1H), 5.07 (s, 2H), 4.33 (q, J=6.0 Hz, 1H), 3.82-3.80 (m, 2H), 3.57 (d, J=6.9 Hz, 1H), 3.41-3.39 (m, 1H), 2.87 (t, J=7.0 Hz, 1H), 1.21 (d, J=6.2 Hz, 3H).

Example 222: 3-[5-Chloro-2-(1-phenyl-azetidin-3-ol)-phenoxy]-azetidine

Step A: Preparation of 1-phenyl-azetidin-3-ol

The mixture of azetidin-3-ol (2 mmol), bromobenzene (2 mmol), Pd(OAc)₂ (0.1 mmol), 2-(di-tert-butylphosphino)biphenyl (0.2 mmol) and NaOtBu (3 mmol) in toluene (3 mL) was heated at 100° C. for 1 h. The mixture was cooled to rt and purified via PTLC providing the title compound (15 mg).

Step B: Preparation of 3-[5-Chloro-2-(1-phenyl-azetidin-3-ol)-phenoxy]-azetidine

The mixture of the title compound of Step A (15 mg), 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (0.2 mmol) and cyanomethylenetri-n-butylphosphorane (0.2 mmol) in toluene (2 mL) was heated at 120° C. in a microwave reactor for 1 h. The mixture was cooled to rt and purified via PTLC providing the title compound (20 mg). This compound was dissolved in CH₂Cl₂ (5 mL) and TFA (1 mL) was added. The mixture was stirred at rt for 4 h and concentrated to provide the title compound (25 mg). MS (ESI): mass calcd. for C₁₈H₁₉ClN₂O₂, 330.1; m/z found, 331.1 [M+H]⁺. ¹H NMR (MeOD): 7.26-6.58 (m, 8H), 5.20-5.05 (m, 2H), 4.55-4.45 (m, 2H), 4.37-4.28 (m, 2H), 4.25-4.16 (m, 2H), 3.88-3.85 (m, 2H).

Examples 223-225 were prepared similar to Example 222 using the appropriately substituted hydroxyazetidine.

Example 223: (±)-3-[5-Chloro-2-(trans-1-benzyl-2-methyl-azetidin-3-ol)-phenoxy]-azetidine

Prepared from trans-(±)-1-benzyl-2-methyl-azetidin-3-ol. MS (ESI): mass calcd. for C₂₀H₂₃ClN₂O₂, 358.1; m/z found, 359.1 [M+H]⁺. ¹H NMR (MeOD): 7.61-7.43 (m, 5H), 7.03-6.87 (m, 3H), 5.23-5.16 (m, 1H), 4.88-4.78 (m, 1H), 4.76-4.65 (m, 1H), 4.63-4.45 (m, 5H), 4.29-4.19 (m, 2H), 4.18-4.09 (m, 1H), 1.40 (d, J=6.7 Hz, 3H).

Example 224: 3-[5-Chloro-2-(1-Isopropyl-azetidin-3-ol)-phenoxy]-azetidine

Prepared from 1-isopropyl-azetidin-3-ol. MS (ESI): mass calcd. for C₁₅H₂₁ClN₂O₂, 296.1; m/z found, 297.0 [M+H]⁺. ¹H NMR (MeOD): 7.70 (dd, J=8.7, 2.5 Hz, 1H), 6.78-6.67 (m, 2H), 5.04-4.97 (m, 1H), 4.76-4.67 (m, 1H), 3.98-3.92 (m, 2H), 3.80-3.67 (m, 4H), 3.34-3.26 (m, 2H), 2.53-2.46 (m, 1H), 0.98 (d, J=6.3 Hz, 6H).

Example 225: 3-[5-Chloro-2-(1-benzhydryl-azetidin-3-ol)-phenoxy]-azetidine

Prepared from 1-benzhydryl-azetidin-3-ol. MS (ESI): mass calcd. for C₂₅H₂₅ClN₂O₂, 420.2; m/z found, 421.0 [M+H]⁺. ¹H NMR (MeOD): 7.58-7.39 (m, 10H), 7.02-6.81 (m, 3H), 5.81 (s, 1H), 5.19-5.10 (m, 2H), 4.67-4.50 (m, 4H), 4.39-4.31 (m, 2H), 4.23-4.16 (m, 2H).

Example 226: 3-[5-Chloro-2-(1-azetidin-3-ol)-phenoxy]-azetidine

Prepared according to the procedure of Example 222 Step B using 3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester. MS (ESI): mass calcd. for C₁₂H₁₅ClN₂O₂, 254.1; m/z found, 255.1 [M+H]⁺. ¹H NMR (MeOD): 7.00 (dd, J=8.6, 2.4 Hz, 1H). 6.91 (d, J=2.4 Hz, 1H), 6.83 (d, J=8.6 Hz, 1H), 5.22-5.11 (m, 2H), 4.62-4.53 (m, 4H), 4.31-4.22 (m, 4H).

Example 227: 3-[5-Chloro-2-(1-Isopropyl-azetidin-3-ol)-phenoxy]-1-isopropyl-azetidine

To the title compound of Step 226 (100 mg) in CH₂Cl₂ (50 mL) was added acetone (100 μL) and NaBH₃CN (1 mL, 1M in CH₂Cl₂). The mixture was stirred at rt for 16 h. Then, NaOH solution (2 mL, 1M in H₂O) was added. After 1 h, the organic layer was separated and concentrated. PTLC provided the title compound (20 mg). MS (ESI): mass calcd. for C₁₈H₂₇ClN₂O₂, 338.2; m/z found, 339.3 [M+H]⁺. ¹H NMR (CDCl₃): 6.85 (dd, J=8.6, 2.4 Hz, 1H). 6.63 (d, J=2.4 Hz, 1H), 6.58 (d, J=8.6 Hz, 1H), 4.83-4.67 (m, 2H), 3.96-3.76 (m, 4H), 3.26-3.05 (m, 4H), 2.47-2.38 (m, 2H), 1.00 (d, J=6.1 Hz, 12H).

Example 228: 3-[5-Chloro-2-(3-phenyl-cyclobutoxy)-phenoxy]-azetidine

Step A: Preparation of 3-phenyl-cyclobutanol

To the solution of 3-phenyl-cyclobutanone (100 mg) in THF (10 mL) was added LiAlH₄ (0.2 mL, 2M in THF). The mixture was stirred at rt for 2 h, then 2M NaOH (1 mL) was added. The organic layer was concentrated and purified by PTLC providing the title compound (80 mg).

Step B: Preparation of 3-[5-Chloro-2-(3-phenyl-cyclobutoxy)-phenoxy]-azetidine

The mixture of the title compound of Step A (80 mg), 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (200 mg) and cyanomethylenetri-n-butylphosphorane (1.0 mmol) in toluene (2 mL) was heated at 120° C. in a microwave reactor for 1 h. The mixture was cooled to rt and purified via PTLC providing 3-[5-chloro-2-(3-phenyl-cyclobutoxy)-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester (120 mg). The ester was re-dissolved into CH₂Cl₂ (10 mL), and TFA (2 mL) was added. The mixture was stirred at rt for 4 h then concentrated to give the title compound (168 mg). MS (ESI): mass calcd. for C₁₉H₂₀ClNO₂, 329.1; m/z found, 330.1 [M+H]⁺. ¹H NMR (MeOD): 7.26-6.64 (m, 8H), 5.30-5.15 (m, 2H), 4.95-4.83 (m, 2H), 4.60-4.52 (m, 1H), 3.78-3.65 (m, 1H), 2.68-2.58 (m, 4H).

Example 229: 3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-tert-butyl-azetidine

Step A: Preparation of 1-tert-butyl-azetidin-3-ol

To a solution of tert-butylamine (10 mmol) in isopropylalcohol (20 mL) was added dropwise epichlorohydrine (10 mmol). The mixture was stirred at 25° C. for 16 h. After concentration, the residue was re-dissolved in acetonitrile (20 mL) and triethylamine (20 mmol) was added. The mixture was heated at 100° C. for 24 h, cooled to rt and filtered. The filtrate was concentrated providing 1-tert-butyl-azetidin-3-ol (1.1 g). MS (ESI): mass calcd. for C₇H₁₅NO, 129.1; m/z found, 130.1 [M+H]⁺. ¹H NMR (CDCl₃): 6.15-5.70 (br s, 1H), 4.84-4.72 (m, 1H), 4.24-4.12 (m, 2H), 4.03-3.87 (m, 2H), 1.37 (s, 9H).

Step B: Preparation of 3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-tert-butyl-azetidine

To a solution of the title compound of Step A (3 mmol), and triethylamine (6 mmol) in CH₂Cl₂ (50 mL), was added MeSO₃Cl (4 mmol). The mixture was stirred at 25° C. for 16 h. After concentration, ⅓ of the residue was dissolved in MeCN (20 mL). Next, 5-bromo-2-(3-fluoro-benzyloxy)-phenol (0.5 mmol) and K₂CO₃ (2 mmol) were added. The mixture was stirred at 100° C. for 16 h, concentrated and purified via PTLC providing the title compound (189 mg). MS (ESI): mass calcd. for C₂OH₂₃BrFNO₂, 407.1; m/z found, 408.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.37-7.28 (m, 1H), 7.19-7.12 (m, 2H), 7.04-6.95 (m, 2H), 6.84-6.63 (m, 2H), 5.08 (s, 2H), 4.78-4.48 (m, 1H), 3.68-3.62 (m, 2H), 3.35-3.26 (m, 2H), 1.00 (s, 9H).

Example 230-231 was prepared by the procedure of Example 229 using the appropriately substituted phenols.

Example 230: 1-tert-Butyl-3-[5-chloro-2-(3-trifluoromethyl-benzyloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₂₁H₂₃ClF₃NO₂, 413.1; m/z found, 413.9 [M+H]⁺. ¹H NMR (CDCl₃): 7.75-7.46 (m, 4H), 6.90-6.65 (m, 3H), 5.12 (s, 2H), 4.80-4.71 (m, 1H), 3.71-3.62 (m, 2H), 3.35-3.26 (m, 2H), 0.99 (s, 9H).

Example 231: 1-tert-Butyl-3-[5-chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-azetidine

MS (ESI): mass calcd. for C₂₂H₂₅ClF₃NO₂, 427.2; m/z found, 428.3 [M+H]⁺. ¹H NMR (CDCl₃): 7.68-7.42 (m, 4H), 6.78-6.62 (m, 3H), 5.32-5.23 (m, 1H), 4.78-4.68 (m, 1H), 3.70-3.62 (m, 2H), 3.33-3.25 (m, 2H), 1.65 (d, J=6.4 Hz, 3H), 0.99 (s, 9H).

Example 232: 3-[5-Bromo-2-(5-trifluoromethyl-furan-2-ylmethoxy)-benzyl]-azetidine

Step A: Preparation of 3-(Methoxy-methyl-carbamoyl)-azetidine-1-carboxylic acid tert-butyl ester

To a solution of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester (3.5 g, 17 mmol) in DMF (50 mL) was added O,N-dimethyl-hydroxylamine hydrochloride (3.4 g, 34 mmol), triethylamine (9.6 mL, 69 mmol), HATU (13.4 g, 34.6 mmol) and DCM (125 mL). After stirring for 16 h, saturated NaHCO₃ solution and ethyl acetate were added. The aqueous portion was extracted three times with ethyl acetate. The combined organic fractions were dried (Na₂SO₄) and concentrated and the crude product was purified using RP HPLC (basic conditions) to provide the title compound (3.5 g, 83%) MS (ESI): mass calcd. for C₁₁H₂₀N₂O₄, 244.1; m/z found, 189.1 [M-t-Bu]⁺. ¹H NMR (CDCl₃): 4.14-4.03 (m, 2H), 4.05 (t, J=8.7 Hz, 2H), 3.66 (s, 3H), 3.63-3.59 (m, 1H), 3.21 (s, 1H), 1.43 (s, 9H).

Step B: Preparation of 3-(2-Methoxy-benzoyl)-azetidine-1-carboxylic acid tert-butyl ester

To a solution of 3-(methoxy-methyl-carbamoyl)-azetidine-1-carboxylic acid tert-butyl ester (3.48 g, 14.2 mmol) in dry ether (150 mL) at 0° C. was added 2-methoxylphenylmagnesium bromide (1.0M in THF, 17 mL, 17 mmol). The reaction was allowed to slowly warm to rt and stirred for 36 h. Then a solution of 1M KHSO₄ and EtOAc were added and the aqueous portion was extracted once with EtOAc. The combined organic fractions were dried (Na₂SO₄) and concentrated to provide the title compound. This material was used in subsequent reactions without additional purifications. MS (ESI): mass calcd. for C₁₆H₂₁NO₄, 291.1; m/z found, 236.1 [M-t-Bu]⁺. ¹H NMR (CDCl₃): 7.83 (dd, J=7.8, 1.8 Hz, 1H), 7.51 (ddd, J=8.5, 7.3, 1.8 Hz, 1H), 7.06-6.95 (m, 2H), 4.13-4.03 (m, 5H), 3.90 (s, 3H), 1.44 (s, 9H).

Step C: Preparation of 3-(2-Methoxy-benzyl)-azetidine-1-carboxylic acid tert-butyl ester

To a solution of 3-(2-methoxy-benzoyl)-azetidine-1-carboxylic acid tert-butyl ester (2.1 g, 7.2 mmol) in methanol (50 mL) was added sodium borohydride (1.08 g, 28.8 mmol). After stirring for 36 h, saturated sodium bicarbonate solution and EtOAc were added. The aqueous portion was extracted three times with EtOAc and the combined organic were dried (Na₂SO₄) and concentrated. To a solution of this material in ethanol (50 mL) was added 10% Pd/C. This reaction was then placed on a Parr hydrogenation apparatus with 60 psi of hydrogen gas. After 72 h, the reaction mixture was filtered through a pad of Celite and the filtrate concentrated. The crude product was purified by RP HPLC (basic conditions) to provide the title compound (370 mg, 19%). MS (ESI): mass calcd. for C₁₆H₂₃NO₃, 277.2; m/z found, 222.2 [M-t-Bu]⁺. ¹H NMR (CDCl₃): 7.23-7.10 (m, 1H), 7.06 (d, J=7.3 Hz, 1H), 6.92-6.77 (m, 2H), 3.96 (t, J=8.0 Hz, 2H), 3.81 (s, 3H), 3.65-3.63 (m, 2H), 2.94-2.78 (m, 5H), 1.44 (s, 9H).

Step D: Preparation of 2,2,2-Trifluoro-1-[3-(2-methoxy-benzyl)-azetidin-1-yl]-ethanone

To a solution of 3-(2-methoxy-benzyl)-azetidine-1-carboxylic acid tert-butyl ester (370 mg, 1.3 mmol) in DCM (10 mL) was added TFA (3 mL). After stirring for 16 h, TLC analysis indicated complete consumption of the starting material. To quench the reaction, saturated NaHCO₃ solution and EtOAc were added. The aqueous portion was extracted twice with EtOAc and the combined organic extracts were dried (Na₂SO₄) and concentrated. To a solution of this material in DCM (20 mL) was added triethylamine (370 μL, 2.60 mmol) followed by trifluoroacetic anhydride (204 μL, 1.50 mmol). After 1 h, saturated NaHCO₃ solution and EtOAc were added. The aqueous portion was extracted twice with EtOAc and the combined organic extracts were dried (Na₂SO₄) and concentrated to provide the title compound (274 mg, 75%). MS (ESI): mass calcd. for C₁₃H₁₄F₃NO₂, 273.1; m/z found, 274.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.26-7.20 (m, 1H), 7.07 (dd, J=7.4, 1.6 Hz, 1H), 6.94-6.82 (m, 2H), 4.41 (dd, J=9.6, 8.4 Hz, 1H), 4.23-4.14 (m, 1H), 4.12-4.08 (m, 1H), 3.93-3.84 (m, 1H), 3.82 (s, 3H), 3.18-3.00 (m, 1H), 2.95-2.91 (m, 2H).

Step E: Preparation of 1-[3-(5-Bromo-2-methoxy-benzyl)-azetidin-1-yl]-2,2,2-trifluoro-ethanone

To a solution of 2,2,2-trifluoro-1-[3-(2-methoxy-benzyl)-azetidin-1-yl]-ethanone (95 mg, 0.35 mmol) in acetone (2 mL) and water (2 mL) was added NaBr (143 mg, 1.40 mmol) followed by Oxone (210 mg, 0.35 mmol). After 5 h, 10% sodium metabisulfite solution was added. After 1 h, EtOAc was added and the aqueous portion extracted twice with EtOAc. The combined organics were dried (Na₂SO₄) and concentrated. The crude product was purified by RP HPLC (basic conditions) to provide the title compound (66 mg, 53%). MS (ESI): mass calcd. for C₁₃H₁₃BrF₃NO₂, 352.1; m/z found, 354.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.32 (dd, J=8.7, 2.5 Hz, 1H), 7.17 (d, J=2.5 Hz, 1H), 6.75 (t, J=10.2 Hz, 1H), 4.43 (dd, J=9.6, 8.4 Hz, 1H), 4.26-4.14 (m, 1H), 4.09 (dd, J=9.6, 5.7 Hz, 1H), 3.89 (dd, J=10.7, 5.7 Hz, 1H), 3.81 (s, 3H), 3.14-2.96 (m, 1H), 2.90 (d, J=7.8 Hz, 2H).

Step F: Preparation of 1-[3-(5-Bromo-2-hydroxy-benzyl)-azetidin-1-yl]-2,2,2-trifluoro-ethanone

To a solution of 1-[3-(5-bromo-2-methoxy-benzyl)-azetidin-1-yl]-2,2,2-trifluoro-ethanone (66 mg, 0.19 mmol) in dry DCM (10 mL) at 0° C. was added BBr₃ (1.0M in DCM, 370 mL, 0.37 mmol). After warming to rt overnight, saturated NaHCO₃ solution and EtOAc were added. The aqueous portion was extracted twice with EtOAc and the combined organic extracts were dried (Na₂SO₄) and concentrated to provide the title compound (59 mg, 92%). MS (ESI): mass calcd. for C₁₂H₁₁BrF₃NO₂, 337.0; m/z found, 338.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.23-7.10 (m, 2H), 6.70 (t, J=8.7 Hz, 1H), 4.53-4.40 (m, 1H), 4.27-4.11 (m, 2H), 3.97 (dd, J=10.7, 6.0 Hz, 1H), 3.17-3.01 (m, 1H), 3.01-2.78 (m, 2H).

Step G: Preparation of 1-{3-[5-Bromo-2-(5-trifluoromethyl-furan-2-ylmethoxy)-benzyl]-azetidin-1-yl}-2,2,2-trifluoro-ethanone

To a solution of 1-[3-(5-bromo-2-hydroxy-benzyl)-azetidin-1-yl]-2,2,2-trifluoro-ethanone (59 mg, 0.17 mmol) in DMF (10 mL) was added KI (40 mg, 0.24 mmol), Cs₂CO₃ (170 mg, 0.51 mmol) and 2-bromomethyl-5-trifluoromethyl-furan (56 mg, 0.24 mmol). After 16 h, saturated sodium bicarbonate solution and EtOAc were added. The aqueous portion was extracted three times with EtOAc and the combined organic were dried (Na₂SO₄) and concentrated. The crude product was purified by RP HPLC (basic conditions) to provide the title compound (76 mg, 91%). MS (ESI): mass calcd. for C₁₈H₁₄BrF₆NO₃, 486.2; m/z found, 488.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.34 (dd, J=8.7, 2.5 Hz, 1H), 7.21 (d, J=2.5 Hz, 1H), 6.89-6.76 (m, 2H), 6.48 (d, J=3.4 Hz, 1H), 5.02 (s, 2H), 4.40 (dd, J=9.6, 8.4 Hz, 1H), 4.22-4.11 (m, 1H), 4.08-4.02 (m, 1H), 3.84 (dd, J=10.7, 5.7 Hz, 1H), 3.11-2.97 (m, 1H), 2.97-2.82 (m, 2H).

Step H: Preparation of 3-[5-Bromo-2-(5-trifluoromethyl-furan-2-ylmethoxy)-benzyl]-azetidine

To a solution of 1-{3-[5-bromo-2-(5-trifluoromethyl-furan-2-ylmethoxy)-benzyl]-azetidin-1-yl}-2,2,2-trifluoro-ethanone (76 mg, 0.16 mmol) in methanol (10 mL) was added K₂CO₃ (94 mg, 0.70 mmol). After 1 h, TLC analysis indicated complete consumption of the starting material. Brine and EtOAc were added to the reaction mixture and the aqueous portion was extracted with EtOAc (3×). The combined organic layers were dried. The crude product was purified by RP HPLC (basic conditions) to provide the title compound (50 mg, 76%). MS (ESI): mass calcd. for C₁₆H₁₅BrF₃NO₂, 390.2; m/z found, 393.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.50-7.41 (m, 1H), 7.35-7.26 (m, 1H), 6.89-6.79 (m, 2H), 6.53 (s, 1H), 5.05 (s, 2H), 4.43-4.20 (m, 1H), 3.63 (t, J=8.2 Hz, 2H), 3.44 (t, J=7.7 Hz, 2H), 2.85 (d, J=7.6 Hz, 2H).

Example 233: 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxymethyl]-azetidine

Prepared similar to Example 1 using 3-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester. MS (ESI): mass calcd. for C₁₇H₁₇BrClNO₂, 381.0: m/z found, 382.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.45 (s, 1H), 7.35-7.21 (m, 3H), 7.15-6.96 (m, 2H), 6.77 (d, J=8.5, 1H), 5.04 (s, 2H), 4.16 (d, J=6.4, 2H), 3.81 (m, 2H), 3.63 (m, 1H), 3.62-3.52 (m, 1H), 3.21 (m, 1H), 2.17 (m, 1H).

Example 234: 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxymethyl]-1-methyl-azetidine

Prepared from Example 233 using general procedure 5. MS (ESI): mass calcd. for C₁₈H₁₉BrClNO₂, 395.0; m/z found, 396.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.52 (d, J=2.5, 1H), 7.40 (s, 1H), 7.36-7.22 (m, 4H), 6.74 (d, J=8.7, 1H), 5.04 (s, 2H), 4.45 (s, 2H), 4.23-4.15 (m, 1H), 3.64 (s, 2H), 2.93 (s, 2H), 2.35 (s, 3H).

Example 235: 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxymethyl]-azetidin-3-ol

Step A: Preparation of 1-Boc-3-[5-bromo-2-(3-chloro-benzyloxy)-phenoxymethyl]-azetidin-3-ol

The mixture of the title compound of Example 215 Step B (2.3 mmol), 5-bromo-2-(3-chloro-benzyloxy)-phenol (1.3 mmol), and cyanomethylenetri-n-butylphosphorane (2 mmol) in toluene (5 mL) was heated at 150° C. in a microwave reactor for 1 h. The mixture was cooled to rt and purified by PTLC providing the title compound (580 mg). MS (ESI): mass calcd. for C₂₂H₂₅BrClNO₅, 497.1; m/z found, 504.2 [M-OH+Na]⁺. ¹H NMR (CDCl₃): 7.52-7.23 (m, 4H), 6.99-6.68 (m, 3H), 5.70-5.10 (br S, 1H), 5.04 (s, 2H), 4.99-4.97 (m, 2H), 4.50-4.46 (m, 4H), 1.45 (s, 9H).

Step B: 3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxymethyl]-azetidin-3-ol

The the title compound of Step A (160 mg) was dissolved in CH₂12 (20 mL), and TFA (3 mL) was added. The mixture was stirred at rt for 4 h and concentrated. The resulting residue was dissolved into MeOH (20 mL), and Dowex 66 ion-exchange resin (Dowex hydroxide, weakly basic anion, Macroporous) was added to adjust the pH to 7. The resin was filtered and the filtrate concentrated providing the title compound (120 mg). MS (ESI): mass calcd. for C₁₇H₁₇BrClNO₃, 397.0; m/z found, 382.2 [M-OH+H]+. ¹H NMR (MeOD): 7.52-7.28 (m, 4H), 6.97-6.81 (m, 3H), 5.18-5.15 (m, 2H), 5.12 (s, 2H), 4.73-4.68 (m, 4H).

Example 236: 3-[1-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-ethyl]-azetidin-3-ol

Prepared according to Example 235 using 3-ethyl-3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester. MS (ESI): mass calcd. for C₁₈H₁₉BrClNO₃, 411.0; m/z found, 396.0 [M-OH+H]⁺. ¹H NMR (MeOD): 7.52-7.27 (m, 4H), 6.98-6.80 (m, 3H), 5.57-5.48 (m, 1H), 5.12 (s, 2H), 4.73-4.61 (br s, 4H), 1.63-1.57 (m, 3H).

Example 237: 3-[5-Bromo-2-(3-chloro-benzyloxy)-benzyloxy]-azetidine

Step A: Preparation of [5-Bromo-2-(3-chloro-benzyloxy)-phenyl]-methanol

To a solution of 5-bromo-2-(3-chloro-benzyloxy)-benzaldehyde (6.0 g, 18.4 mmol) in MeOH (90 mL) at rt was added NaBH₄ (1.07 g, 27.7 mmol) over 1 h. After 18 h at rt, H₂O was added (5 mL) and the reaction concentrated to a residual mass, which was dissolved into EtOAc (150 mL). This EtOAc solution was washed with H₂O (2×100 mL) and dried to yield the title compound as a light yellow (6.0 g, 100%). MS (ESI): mass calcd. for C₁₄H₁₂BrClO, 327.6; m/z found, 328.3 [M+H]⁺. ¹H NMR (CDCl₃) 7.48 (d, J=2.5 Hz, 1H), 7.42-7.20 (m, 5H), 6.76 (d, J=8.7 Hz, 1H), 5.07 (d, J=19.2 Hz, 2H), 4.69 (d, J=17.5 Hz, 2H), 2.15 (t, J=10.0 Hz, 1H).

Step B. 5-Bromo-2-(3-chloro-benzyloxy)-benzyl chloride

The title compound of Step A was dissolved into CH₂Cl₂ (8 mL) and thionyl chloride (114 mg, 0.95 mmol) was added at rt. The reaction mixture was stirred for 2 h and concentrated to yield the title compound (300 mg). ¹H NMR (CDCl₃): 7.51 (d, J=2.5 Hz, 1H), 7.48-7.22 (m, 6H), 6.76 (t, J=11.1 Hz, 1H), 5.14-4.99 (m, 2H), 4.65 (d, J=14.7 Hz, 2H).

Step C. 3-[5-Bromo-2-(3-chloro-benzyloxy)-benzyloxy]-azetidine

To a DMF (5 mL) solution of 3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (150 mg, 0.87 mmol) at rt was added 60% NaH (36 mg, 0.91 mmol). The reaction mixture was stirred at rt for 0.5 h. Then a DMF solution of the title compound of Step B (300 mg, 0.87 mmol) was added. After 18 h, the reaction mixture was partitioned between EtOAc and H₂O. The organic phase was dried and concentrated to yield the title compound (380 mg). This material was purified by chromatography (SiO₂) using 0-25% EtOAc in hexanes to give 3-[5-bromo-2-(3-chloro-benzyloxy)-benzyloxy]-azetidine-1-carboxylic acid tert-butyl ester (70 mg, 37%). This compound was treated with 4M HCl in dioxane and stirred 6 h at rt and concentrated. Purification by RP HPLC (basic system) gave the title compound (26 mg, 7%) MS (ESI): mass calcd. for C₁₇H₁₇BrClNO₂, 381.7; m/z found, 383.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.52 (d, J=2.5 Hz, 1H), 7.41 (s, 1H), 7.36-7.21 (m, 4H), 6.74 (d, J=8.7 Hz, 1H), 5.03 (s, 2H), 4.49-4.39 (m, 3H), 3.68 (m, 4H), 1.75 (s, 1H).

Example 238: 3-[5-Chloro-2-(3-chloro-benzyloxy)-benzyloxy]-azetidine

Prepared according to Example 237 using 5-chloro-2-(3-chloro-benzyloxy)-benzaldehyde. MS (ESI): mass calcd. for C₁₇H₁₇Cl₂NO₂, 337.06; m/z found, 338.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.43-7.15 (m, 6H), 6.79 (d, J=8.7 Hz, 1H), 5.04 (s, 2H), 4.49-4.39 (m, 3H), 3.71-3.67 (m, 3H), 1.92 (m, 1H), 1.90-1.83 (m, 1H).

Example 239: 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-3-methyl-[1,2,4]oxadiazole

Step A: Preparation of 3-(5-Chloro-2-ethoxycarbonylmethoxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester

To 3-(5-Chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (1.5 g, 5.0 mmol) in DMF (20 mL) was added Cs₂CO₃ (2.1 g, 6.4 mmol), KI (0.84 g, 5.0 mmol) and bromoethyl acetate (0.84 g, 0.55 mL, 5.0 mmol). After 18 h, H₂O was added and the mixture extracted with EtOAc (2×). The combined organics were washed with brine and dried. Silica gel chromatography (5-30% EtOAc in hexanes) gave 1.95 g (99%) of the title compound as a clear oil. ¹H NMR (CDCl₃): 6.91 (dd, J=8.7, 2.4 Hz, 1H), 6.79 (d, J=8.7 Hz, 1H), 6.58 (d, J=2.4 Hz, 1H), 4.91-4.87 (m, 1H), 4.65 (s, 2H), 4.32-4.25 (m, 4H), 4.01 (dd, J=10.5, 4.2 Hz, 2H), 1.44 (s, 9H), 1.30 (t, J=7.1 Hz, 3H).

Step B: Preparation of 3-(2-Carboxymethoxy-5-chloro-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester

To the title compound from Step A (1.70 g, 4.40 mmol) in MeOH (10 mL) was added 4N NaOH (10 mL). After 2 h, CH₂Cl₂ was added and the mixture acidified with 1N KHSO₄ (50 mL) then extracted with CH₂Cl₂ (2×). The combined organics were dried to give a 0.90 g (57%) of the title compound as a white solid that was used without further purification. MS (ESI): mass calcd. for C₁₆H₂₀ClNO₆, 357.1; m/z found, 380.1 [M+Na]⁺. ¹H NMR (400 MHz): 6.92 (dd, J=8.6, 2.3 Hz, 1H), 6.85 (d, J=8.7 Hz, 1H), 6.59 (d, J=2.3 Hz, 1H), 4.92-4.86 (m, 1H), 4.67 (s, 2H), 4.31 (dd, J=9.9, 6.5 Hz, 2H), 4.07 (dd, J=10.0, 4.1 Hz, 2H), 1.45 (s, 9H).

Step C: Preparation of 3-[5-Chloro-2-(3-methyl-[1,2,4]oxadiazol-5-ylmethoxy)-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester

To the title compound of Step B (0.15 g, 0.42 mmol) in CH₂Cl₂ (4 mL) was added DMF (catalytic) and 2M COCl₂ in CH₂Cl₂ (0.3 mL, 0.6 mmol). After 2 h, the reaction was concentrated and THF (2 mL) was added. This solution was added to N-hydroxy-acetamidine (0.035 g, 0.46 mmol) and N,N-diisopropylethylamine (0.065 g, 0.088 mL, 0.50 mmol) in THF (2 mL). The mixture was then heated for 20 min at 155° C. in a microwave reactor, cooled to rt and concentrated. Silica gel chromatography (5-30% EtOAc in hexanes) gave 0.155 g (93%) of the title compound as a clear oil. MS (ESI): mass calcd. for C₁₈H₂₂ClN₃O₅, 395.1; m/z found, 295.3 [M−100]⁺. ¹H NMR (400 MHz): 6.94 (d, J=8.6 Hz, 1H), 6.91 (dd, J=8.6, 2.2 Hz, 1H), 6.57 (d, J=2.1 Hz, 1H), 5.27 (s, 2H), 4.89-4.85 (m, 1H), 4.32-4.29 (m, 2H), 4.04 (dd, J=10.4, 4.2 Hz, 2H), 2.43 (s, 3H), 1.45 (s, 9H).

Step D: Preparation of 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-3-methyl-[1,2,4]oxadiazole hydrochloride

Prepared from the title compound of Step B using general procedure 1. MS (ESI): mass calcd. for C₁₃H₁₄ClN₃O₃, 295.1; m/z found, 296.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 9.30 (s, 2H), 7.14 (d, J=8.7 Hz, 1H), 7.05 (dd, J=8.7, 2.4 Hz, 1H), 6.96 (d, J=2.4 Hz, 1H), 5.52 (s, 2H), 5.10-5.05 (m, 1H), 4.42 (dd, J=12.5, 6.7 Hz, 2H), 4.01 (dd, J=12.5, 4.8 Hz, 2H) 2.36 (s, 3H).

The compounds in Examples 240-243 were synthesized according to Example 239 using the appropriately substituted N-hydroxyamidine.

Example 240: 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-3-cyclobutyl-[1,2,4]oxadiazole

MS (ESI): mass calcd. for C₁₆H₁₈ClN₃O₃, 335.1; m/z found, 336.2 [M+H]⁺. ¹H NMR (CDCl₃): 6.95 (d, J=8.6 Hz, 1H), 6.87 (dd, J=8.6, 2.3 Hz, 1H), 6.62 (s, 1H), 5.28 (s, 2H), 4.99-4.89 (m, 1H), 3.98-3.66 (m, 5H), 2.41-2.36 (m, 4H), 2.17-1.98 (m, 2H).

Example 241: 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-3-cyclopropyl-[1,2,4]oxadiazole hydrochloride

MS (ESI): mass calcd. for C₁₅H₁₆ClN₃O₃, 321.1; m/z found, 322.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 9.31 (s, 2H), 7.12 (d, J=8.8 Hz, 1H), 7.05 (dd, J=8.7, 2.4 Hz, 1H), 6.96 (d, J=2.4 Hz, 1H), 5.49 (s, 2H), 5.09-5.04 (m, 1H), 4.42 (dd, J=12.2, 6.6 Hz, 2H), 4.03-3.99 (m, 2H), 2.17-2.13 (m, 1H), 1.11-1.07 (m, 2H), 0.90-0.87 (m, 2H).

Example 242: 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-3-isopropyl-[1,2,4]oxadiazole hydrochloride

MS (ESI): mass calcd. for C₁₅H₁₈ClN₃O₃, 323.1; m/z found, 324.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 9.28 (s, 2H), 7.14 (d, J=8.7 Hz, 1H), 7.06 (dd, J=8.7, 2.4 Hz, 1H), 6.97 (d, J=2.4 Hz, 1H), 5.51 (s, 2H), 5.10-5.05 (m, 1H), 4.43 (dd, J=12.3, 6.6 Hz, 2H), 4.02 (dd, J=12.3, 4.7 Hz, 2H), 3.12-3.07 (m, 1H), 1.28 (d, J=6.9 Hz, 6H).

Example 243: 5-[2-(Azetidin-3-yloxy)-4-chloro-phenoxymethyl]-3-ethyl-[1,2,4]oxadiazole hydrochloride

MS (ESI): mass calcd. for C₁₄H₁₆ClN₃O₃, 309.1; m/z found, 310.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 9.34 (s, 2H), 7.14 (d, J=8.7 Hz, 1H), 7.06 (dd, J=8.7, 2.4 Hz, 1H), 6.97 (d, J=2.4 Hz, 1H), 5.51 (s, 2H), 5.10-5.05 (m, 1H), 4.42 (dd, J=12.6, 6.7 Hz, 2H), 4.02 (dd, J=12.5, 4.9 Hz, 2H), 2.75 (q, J=7.6 Hz, 2H), 1.26 (t, J=7.6 Hz, 2H).

Compounds in Examples 244-278 were synthesized according to general procedure 6.

Example 244: 3-(5-Bromo-2-phenoxy-phenoxy)-azetidine

MS (ESI): mass calcd. for C₁₅H₁₄BrNO₂, 320.2; m/z found, 322.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.32-7.28 (m, 2H), 7.07-7.05 (m, 2H), 6.94-6.92 (m, 2H), 6.88-6.84 (m, 2H), 4.97-4.91 (m, 1H), 3.85-3.81 (m, 2H), 3.71-3.67 (m, 2H).

Example 245: 3-[5-Bromo-2-(3-bromo-phenoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₅H₁₃Br₂NO₂, 399.1; m/z found, 401.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.21-7.12 (m, 2H), 7.09 (dd, J=8.5, 2.2 Hz, 1H), 7.04-6.98 (m, 1H), 6.91 (d, J=8.5, 1H), 6.88-6.77 (m, 2H), 4.96-4.92 (m, 1H), 3.90-3.78 (m, 2H), 3.72-3.60 (m, 2H).

Example 246: 3-[5-Bromo-2-(3-fluoro-phenoxy)-phenoxy]-azetidine

MS (ESI) mass calcd. for C₁₅H₁₃BrFNO₂, 337.01; m/z found, 338.3 [M+H]⁺. ¹H NMR (CD₃OD) 7.37-7.21 (m, 2H), 7.18 (d, J=2.2 Hz, 1H), 7.03 (d, J=8.6 Hz, 1H), 6.83 (t, J=8.4, 2.4 Hz, 1H), 6.75-6.63 (m, 2H), 5.15 (m, 1H), 4.47 (dd, J=12.4, 6.6 Hz, 2H), 4.05 (dd, J=12.4, 4.7 Hz, 2H).

Example 247: 3-(5-Bromo-2-m-tolyloxy-phenoxy)-azetidine

MS (ESI) mass calcd. for C₁₆H₁₆BrFNO₂, 333.04; m/z found, 334.1 [M+H]⁺. ¹H NMR (CD₃OD) 7.25-7.10 (m, 3H), 6.92 (dd, J=12.9, 8.1 Hz, 2H), 6.80-6.64 (m, 2H), 5.19-5.03 (m, 1H), 4.45 (dd, J=12.7, 6.7 Hz, 2H), 4.09 (dd, J=12.6, 4.9 Hz, 2H).

Example 248: 3-[5-Bromo-2-(3-methoxy-phenoxy)-phenoxy]-azetidine

MS (ESI):mass calcd. for C₁₆H₁₆BrNO₃, 350.2; m/z found, 351.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.18 (t, J=8.1 Hz, 1H), 7.06 (dd, J=8.5, 2.2 Hz, 1H), 6.88 (d, J=8.5 Hz, 1H), 6.83 (d, J=2.2 Hz, 1H), 6.62 (dd, J=8.2, 1.7 Hz, 1H), 6.53-6.45 (m, 2H), 5.00-4.90 (m, 1H), 3.95-3.62 (m, 7H).

Example 249: 3-[5-Bromo-2-(4-fluoro-phenoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₅H₁₃BrFNO₂, 338.2; m/z found, 339.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.05 (dd, J=8.5, 2.2 Hz, 1H), 7.01-6.97 (m, 2H), 6.90-6.88 (m, 2H), 6.82 (dd, J=5.4, 3.1 Hz, 2H), 4.99-4.90 (m, 1H), 3.92-3.64 (m, 4H).

Example 250: 3-[5-Bromo-2-(4-bromo-phenoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₅H₁₃Br₂NO₂, 399.1; m/z found, 401.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.43-7.33 (m, 2H), 7.08 (dd, J=8.5, 2.3 Hz, 1H), 6.88 (d, J=8.5 Hz, 1H), 6.83-6.78 (m, 3H), 4.99-4.90 (m, 1H), 3.95-3.55 (m, 4H).

Example 251: 3-[5-Bromo-2-(4-chloro-phenoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₅H₁₃BrClNO₂, 354.6; m/z found, 355.0 [M+H]⁺. ¹H NMR (MeOD): 7.34-7.22 (m, 2H), 7.18 (d, J=2.2 Hz, 1H), 7.10 (dd, J=8.0, 1.9 Hz, 1H), 7.02 (d, J=8.6 Hz, 1H), 6.94 (t, J=2.2 Hz, 1H), 6.85 (dd, J=8.3, 2.4 Hz, 1H), 5.18-5.10 (m, 1H), 4.50-4.41 (m, 2H), 4.07-4.04 (m, 2H).

Example 252: 3-[5-Bromo-2-(3-chloro-phenoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₅H₁₃BrClNO₂, 354.6; m/z found, 355.0 [M+H]⁺. ¹H NMR (MeOD): 7.34-7.22 (m, 2H), 7.18 (d, J=2.2 Hz, 1H), 7.10 (dd, J=8.0, 1.9 Hz, 1H), 7.02 (d, J=8.6 Hz, 1H), 6.94 (t, J=2.2 Hz, 1H), 6.85 (dd, J=8.3, 2.4 Hz, 1H), 5.18-5.10 (m, 1H), 4.50-4.41 (m, 2H), 4.07-4.04 (m, 2H).

Example 253: 3-[5-Bromo-2-(3-trifluoromethoxy-phenoxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₆H₁₃BrF₃NO₃, 403.0; m/z found, [M+H]⁺. ¹H NMR (MeOD): 7.41 (t, J=8.3 Hz, 1H), 7.31-7.13 (m, 2H), 7.06-7.02 (m, 1H), 7.02-6.97 (m, 1H), 6.93-6.78 (m, 2H), 5.21-5.09 (m, 1H), 4.50-4.47 (m, 2H), 4.06-4.03 (m, 2H), 3.34-3.24 (m, 1H).

Example 254: 3-[5-Bromo-2-(naphthalen-2-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₉H₁₆BrNO₂, 369.0; m/z found, 370.1 [M+H]⁺. ¹H NMR (MeOD): 7.92-7.77 (m, 2H), 7.70 (d, J=8.1 Hz, 1H), 7.49-6.97 (m, 7H), 5.20-5.12 (m, 1H), 4.44 (dd, J=12.5, 6.6 Hz, 2H), 4.05 (dd, J=12.5, 5.0 Hz, 2H).

Example 255: 3-[5-Bromo-2-(naphthalen-1-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₉H₁₆BrNO₂, 369.0; m/z found, 370.1 [M+H]⁺. ¹H NMR (MeOD): 8.25-8.16 (m, 1H), 7.95-7.85 (m, 1H), 7.65-7.16 (m, 6H), 6.95-6.72 (m, 2H), 5.21-5.12 (m, 1H), 4.42 (m, 2H), 4.05 (dd, J=12.5, 5.0 Hz, 2H).

Example 256: 3-(5-Chloro-2-phenoxy-phenoxy)-azetidine

MS (ESI): mass calcd. for C₁₅H₁₄ClNO₂, 275.1; m/z found, 276.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.33-7.26 (m, 2H), 7.11-6.99 (m, 1H), 6.99-6.84 (m, 4H), 6.70 (d, J=1.3 Hz, 1H), 4.97-4.91 (m, 1H), 3.88-3.79 (m, 2H), 3.75-3.64 (m, 2H).

Example 257: 3-[5-Chloro-2-(3-chloro-phenoxy)-phenoxy]-azetidine maleate

MS (ESI): mass calcd. for C₁₅H₁₃Cl₂NO₂, 309.0; m/z found, 310.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.22 (t, J=8.2 Hz, 1H), 7.04 (d, J=8.1 Hz, 1H), 7.01 (dd, J=8.6 Hz, 2.3 Hz, 1H), 6.93 (d, J=8.6 Hz, 1H), 6.89 (t, J=2.1 Hz, 1H), 6.80 (dt, J=5.2, 2.5 Hz, 2H), 6.29 (s, 2H), 5.18-5.08 (m, 1H), 4.44 (d, J=6.7 Hz, 2H), 4.21 (s, 2H).

Example 258: 3-[5-Chloro-2-(4-chloro-phenoxy)-phenoxy]-azetidine trifluoroacetate

MS (ESI): mass calcd. for C₁₅H₁₃Cl₂NO₂, 309.0; m/z found, 310.8 [M+H]⁺. ¹H NMR (CDCl₃): 7.31-7.27 (m, 2H), 7.02 (dd, J=8.7, 2.4 Hz, 1H), 6.91 (d, J=8.6 Hz, 1H), 6.88-6.83 (m, 2H), 6.79 (d, J=2.3 Hz, 1H), 5.11-5.06 (m, 1H), 4.34 (dd, J=11.8, 6.8 Hz, 2H), 4.14 (dd, J=11.7, 5.5 Hz, 2H).

Example 259: 3-(5-Chloro-2-o-tolyloxy-phenoxy)-azetidine trifluoroacetate

MS (ESI): mass calcd. for C₁₆H₁₆ClNO₂, 289.1; m/z found, 290.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.25 (d, J=7.5 Hz, 1H), 7.15 (t, J=7.0 Hz, 1H), 7.07 (t, J=7.4 Hz, 1H), 6.95 (dd, J=8.7, 2.4 Hz, 1H), 6.81 (d, J=2.4 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 6.68 (d, J=8.7 Hz, 1H), 5.10 (s, 1H), 4.34 (s, 2H), 4.19 (s, 2H), 2.24 (s, 3H).

Example 260: 3-[5-Chloro-2-(naphthalen-2-yloxy)-phenoxy]-azetidine

MS (ESI): mass calcd. for C₁₉H₁₆ClNO₂, 325.1; m/z found, 326.2 [M+H]⁺. ¹H NMR (MeOD): 7.90-7.79 (m, 2H), 7.70 (d, J=8.0 Hz, 1H), 7.48-7.03 (m, 7H), 5.20-5.12 (m, 1H), 4.44 (dd, J=12.6, 6.6 Hz, 2H), 4.05 (dd, J=12.6, 5.0 Hz, 2H).

Example 261: 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-benzothiazole

A mixture of 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (0.5 mmol), 2-chloro-benzothiazole (0.5 mmol), and K₂CO₃ (1 mmol) in CH₃CN (3 mL) was heated at 120-150° C. via Microwave for 1 h. The mixture was cooled down and separated through PTLC providing 3-[2-(benzothiazol-2-yloxy)-5-chloro-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester (180 mg). The ester was re-dissolved into CH₂Cl₂ (20 mL), and CF₃COOH (3 mL) was added. The mixture was stirred at 25° C. for 4 h. After concentration, the title compound was obtained (192 mg). MS (ESI): mass calcd. for C₁₆H₁₃ClN₂O₂S, 332.0; m/z found, 333.1 [M+H]⁺. ¹H NMR (MeOD): 7.23-7.07 (m, 4H), 6.92-6.81 (m, 3H), 5.14-5.08 (m, 1H), 4.51 (dd, J=12.5, 6.6 Hz, 2H), 4.23 (dd, J=12.5, 5.0 Hz, 2H).

Example 262: 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-benzooxazole

MS (ESI): mass calcd. for C₁₆H₁₃ClN₂O₃, 316.1; m/z found, 317.1 [M+H]⁺. ¹H NMR (MeOD): 7.83-7.78 (m, 1H), 7.67-7.62 (m, 1H), 7.46-7.41 (m, 2H), 7.26-7.21 (m, 1H), 7.20 (dd, J=8.6, 2.3 Hz, 1H), 7.11 (d, J=2.3 Hz, 1H), 5.26-5.21 (m, 1H), 4.50 (dd, J=12.7, 6.6 Hz, 2H), 4.07 (dd, J=12.7, 4.8 Hz, 2H).

Example 263: 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-[1,8]naphthyridine

MS (ESI): mass calcd. for C₁₇H₁₄ClN₃O₂, 327.1; m/z found, 328.1 [M+H]⁺. ¹H NMR (MeOD): 9.06-9.04 (m, 1H), 8.97 (d, J=4.7 Hz, 1H), 8.74 (d, J=8.9 Hz, 1H), 7.92 (dd, J=8.1, 5.4 Hz, 1H), 7.70 (d, J=8.9 Hz, 1H), 7.25 (d, J=8.6 Hz, 1H), 7.20 (dd, J=8.6, 2.3 Hz, 1H), 7.08 (d, J=2.3 Hz, 1H), 5.27-5.18 (m, 1H), 4.46 (dd, J=12.7, 6.6 Hz, 2H), 3.97 (dd, J=12.7, 4.8 Hz, 2H).

Example 264: 2-[2-(Azetidin-3-yloxy)-4-chloro-phenoxy]-quinoline

MS (ESI): mass calcd. for C₁₈H₁₅ClN₂O₂, 327.1; m/z found, 328.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.75 (s, 1H), 8.12-8.06 (m, 1H), 7.65-7.58 (m, 3H), 7.20 (d, J=8.6 Hz, 1H), 7.04 (dd, J=8.6, 2.3 Hz, 1H), 6.73 (d, J=2.3 Hz, 1H), 4.99-4.88 (m, 1H), 3.86-3.72 (m, 2H), 3.61-3.47 (m, 2H).

Example 265: 4-(5-Chloro-2-phenoxy-phenoxy)-piperidine

MS (ESI): mass calcd. for C₁₇H₁₈ClNO₂, 303.8; m/z found, 304.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.29-7.26 (m, 2H), 7.04-7.01 (m, 1H), 6.99-6.97 (m, 2H), 6.93-6.89 (m, 3H), 4.35-4.30 (m, 2H), 2.95-2.91 (m, 2H), 2.62 (ddd, J=12.3, 8.6, 3.3 Hz, 2H), 1.88-1.82 (m, 2H), 1.57-1.45 (m, 2H).

Example 266: (S)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-pyrrolidine

MS (ESI): mass calcd. for C₁₇H₁₈ClNO₂, 303.1; m/z found, 304.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.09 (t, J=7.7 Hz, 2H), 7.04 (dd, J=8.7, 2.5 Hz, 1H), 6.99 (d, J=2.5 Hz, 1H), 6.87 (d, J=8.7 Hz, 1H), 6.84-6.78 (m, 2H), 4.79 (dd, J=5.7, 4.4 Hz, 1H), 3.06 (d, J=12.8 Hz, 1H), 2.98-2.89 (m, 1H), 2.82-2.71 (m, 2H), 2.32 (s, 3H), 1.99-1.89 (m, 1H), 1.87-1.78 (m, 1H).

Example 267: (R)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-pyrrolidine

MS (ESI): mass calcd. for C₁₇H₁₈ClNO₂, 303.1; m/z found, 304.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.09 (d, J=8.3 Hz, 2H), 7.04 (dd, J=8.7, 2.5 Hz, 1H), 6.98 (d, J=2.5 Hz, 1H), 6.86 (d, J=8.7 Hz, 1H), 6.83-6.79 (m, 2H), 4.79 (t, J=4.8 Hz, 1H), 3.05 (d, J=12.8 Hz, 1H), 2.97-2.89 (m, 1H), 2.78 (d, J=9.3 Hz, 2H), 2.31 (s, 3H), 1.99-1.89 (m, 1H), 1.86-1.77 (m, 1H).

Example 268: (R)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-1-methyl-pyrrolidine

Prepared from Example 261 using general procedure 5. MS (ESI): mass calcd. for C₁₈H₂₀ClNO₂, 317.1; m/z found, 318.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.10 (d, J=8.4 Hz, 2H), 7.00 (dd, J=8.7, 2.5 Hz, 1H), 6.90 (d, J=2.5 Hz, 1H), 6.87-6.79 (m, 3H), 4.84-4.74 (m, 1H), 2.91 (dd, J=10.6, 6.1 Hz, 1H), 2.58 (dd, J=6.9, 6.3 Hz, 2H), 2.54-2.48 (m, 1H), 2.32 (d, J=4.5 Hz, 6H), 2.23-2.16 (m, 1H), 1.98-1.86 (m, 1H).

Example 269: (S)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-pyrrolidine

MS (ESI): mass calcd. for C₁₆H₁₅ClFNO₂, 307.1; m/z found, 308.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.07 (dd, J=8.7, 2.5 Hz, 1H), 7.03-6.96 (m, 3H), 6.92-6.84 (m, 3H), 4.78 (dd, J=5.9, 4.5 Hz, 1H), 3.04 (d, J=12.8 Hz, 1H), 2.95 (dt, J=11.3, 7.4 Hz, 1H), 2.89-2.75 (m, 2H), 2.02-1.92 (m, 1H), 1.85-1.77 (m, 1H).

Example 270: (R)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-pyrrolidine

MS (ESI): mass calcd. for C₁₆H₁₅ClFNO₂, 307.1; m/z found, 308.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.06 (dd, J=8.7, 2.5 Hz, 1H), 7.02-6.96 (m, 3H), 6.91-6.84 (m, 3H), 4.78 (dd, J=5.8, 4.5 Hz, 1H), 3.05 (d, J=12.8 Hz, 1H), 2.96 (dt, J=11.3, 7.4 Hz, 1H), 2.90-2.74 (m, 2H), 2.03-1.92 (m, 1H), 1.85-1.77 (m, 1H).

Example 271: (R)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-1-methyl-pyrrolidine

Prepared from Example 264 using general procedure 5. MS (ESI): mass calcd. for C₁₇H₁₇ClFNO₂, 321.1; m/z found, 322.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.05-6.96 (m, 3H), 6.94-6.86 (m, 3H), 6.81 (d, J=8.7 Hz, 1H), 4.93-4.53 (m, 1H), 2.91 (dd, J=10.6, 6.1 Hz, 1H), 2.63-2.41 (m, 3H), 2.32 (s, 3H), 2.23-2.16 (m, 1H), 1.90-1.81 (m, 1H).

Example 272: (S)-3-(4-Chloro-2-o-tolyloxy-phenoxy)-pyrrolidine

MS (ESI): mass calcd. for C₁₇H₁₈ClNO₂, 303.1; m/z found, 304.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.23 (d, J=6.8 Hz, 1H), 7.11-7.06 (m, 1H), 7.04-6.98 (m, 2H), 6.91 (d, J=2.5 Hz, 1H), 6.86 (d, J=8.7 Hz, 1H), 6.69 (d, J=8.0 Hz, 1H), 4.79 (dd, J=5.6, 4.4 Hz, 1H), 3.04 (d, J=12.9 Hz, 1H), 2.89 (dt, J=11.4, 7.4 Hz, 1H), 2.81-2.71 (m, 2H), 2.29 (s, 3H), 1.98-1.89 (m, 1H), 1.85-1.75 (m, 1H).

Example 273: (S)-3-(4-Chloro-2-m-tolyloxy-phenoxy)-pyrrolidine

MS (ESI): mass calcd. for C₁₇H₁₈ClNO₂, 303.1; m/z found, 304.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.17 (t, J=7.8 Hz, 1H), 7.08-7.02 (m, 2H), 7.04-7.00 (m, 1H), 6.91-6.85 (m, 2H), 6.76-6.66 (m, 2H), 4.81-4.75 (m, 1H), 3.03 (d, J=12.8 Hz, 1H), 2.89 (dt, J=11.3, 7.5 Hz, 1H), 2.80-2.70 (m, 2H), 2.31 (s, 3H), 1.96-1.88 (m, 1H), 1.85-1.74 (m, 1H).

Example 274: (S)-3-[4-Chloro-2-(4-fluoro-3-methyl-phenoxy)-phenoxy]-pyrrolidine

MS (ESI): mass calcd. for C₁₇H₁₇ClFNO₂, 321.1; m/z found, 322.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.05 (dd, J=8.7, 2.5 Hz, 1H), 6.95 (d, J=2.5 Hz, 1H), 6.92 (d, J=8.9 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 6.75 (dd, J=6.2, 3.0 Hz, 1H), 6.72-6.65 (m, 1H), 4.79 (dd, J=5.8, 4.5 Hz, 1H), 3.07 (d, J=12.8 Hz, 1H), 2.98 (dt, J=11.4, 7.4 Hz, 1H), 2.88-2.76 (m, 2H), 2.24 (d, J=1.8 Hz, 3H), 2.00-1.93 (m, 1H), 1.88-1.79 (m, 1H).

Example 275: (S)-3-[4-Chloro-2-(4-chloro-phenoxy)-phenoxy]-pyrrolidine

MS (ESI): mass calcd. for C₁₆H₁₅Cl₂NO₂, 323.1; m/z found, 324.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.27-7.22 (m, 2H), 7.09 (dd, J=8.7, 2.5 Hz, 1H), 7.03 (d, J=2.5 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 6.86-6.75 (m, 2H), 4.76 (dd, J=5.7, 4.5 Hz, 1H), 3.01 (d, J=12.8 Hz, 1H), 2.96-2.74 (m, 3H), 2.01-1.89 (m, 1H), 1.85-1.71 (m, 1H).

Example 276: (S)-3-[4-Chloro-2-(3-chloro-phenoxy)-phenoxy]-pyrrolidine

MS (ESI): mass calcd. for C₁₆H₁₅Cl₂NO₂, 323.1; m/z found, 324.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.21 (t, J=8.1 Hz, 1H), 7.12 (dd, J=8.7, 2.6 Hz, 1H), 7.08 (d, J=2.5 Hz, 1H), 7.03 (ddd, J=8.0, 1.9, 0.9 Hz, 1H), 6.89 (d, J=8.7 Hz, 1H), 6.85 (t, J=2.2 Hz, 1H), 6.80 (ddd, J=8.3, 2.4, 0.9 Hz, 1H), 4.87-4.51 (m, 1H), 3.00 (d, J=12.8 Hz, 1H), 2.94-2.70 (m, 3H), 2.00-1.89 (m, 1H), 1.82-1.71 (m, 1H).

Example 277: (S)-3-[2-(4-Bromo-phenoxy)-4-chloro-phenoxy]-pyrrolidine

MS (ESI): mass calcd. for C₁₆H₁₅BrClNO₂, 367.0; m/z found, 368.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.43-7.35 (m, 2H), 7.10 (dd, J=8.7, 2.6 Hz, 1H), 7.03 (dd, J=8.7, 2.5 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 6.80-6.73 (m, 2H), 4.76 (dd, J=5.9, 4.4 Hz, 1H), 3.01 (d, J=12.8 Hz, 1H), 2.92 (dt, J=11.4, 7.4 Hz, 1H), 2.87-2.72 (m, 2H), 2.02-1.89 (m, 1H), 1.84-1.72 (m, 1H).

Example 278: (S)-3-[4-Chloro-2-(4-isopropyl-phenoxy)-phenoxy]-pyrrolidine

MS (ESI): mass calcd. for C₁₉H₂₂ClNO₂, 331.1; m/z found, 332.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.15 (d, J=8.5 Hz, 2H), 7.07-7.00 (m, 2H), 6.85 (dd, J=11.0, 8.6 Hz, 3H), 4.77 (d, J=4.6 Hz, 1H), 3.04 (d, J=12.8 Hz, 1H), 2.92-2.81 (m, 2H), 2.76-2.70 (m, 2H), 1.95-1.87 (m, 1H), 1.82-1.73 (m, 1H), 1.24 (d, J=6.9 Hz, 6H).

Example 279: (±)-3-[5-Bromo-2-(4-bromo-phenoxy)-phenoxy]-1-ethyl-pyrrolidine

Prepared using 5-bromo-2-(3-bromo-phenoxy)-phenol and (±)-1-ethyl-pyrrolidin-3-ol according to general procedure 7. MS (ESI): mass calcd. for C₁₈H₁₉Br₂NO₂, 439.1; m/z found, 441.0 [M+H]⁺. ¹H NMR (CDCl₃): 7.16-7.12 (m, 2H), 7.08 (dd, J=8.4, 2.2 Hz, 1H), 7.02 (d, J=2.2 Hz, 1H), 7.01-6.98 (m, 1H), 6.93 (d, J=8.5 Hz, 1H), 6.87-6.82 (m, 1H), 4.74 (m, 1H), 3.02 (dd, J=10.7, 6.2 Hz, 1H), 2.69-2.54 (m, 1H), 2.44 (m, 4H), 2.17 (m, 1H), 1.88-1.77 (m, 1H), 1.07 (t, J=7.2 Hz, 3H).

Example 280: 2-(Azetidin-3-yloxy)-4-bromo-phenyl]-phenyl-methanone

Step A: Preparation of 3-[5-Bromo-2-(hydroxy-phenyl-methyl)-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester

To a solution of 3-(5-bromo-2-formyl-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (0.25 g, 0.70 mmol) in CH₂Cl₂ (10 mL) was added a solution of PhMgBr (1M in THF, 1 mL). The reaction was allowed to stir for 15 h then quenched with 1N HCl (4 mL). After 10 min, the mixture was made basic with 1N NaOH (10 mL), and extracted with CH₂Cl₂ (3×20 mL). The organic layers were combined and dried. Chromatography of the resulting residue (SiO₂; EtOAc/Hexanes) gave the title compound (0.24 g, 79%). MS (ESI): mass calcd. for C₂₁H₂₄BrNO₄, 433.1; m/z found, 434.4 [M+H]⁺. ¹H NMR (CDCl₃): 7.41-7.23 (m, 6H), 7.17 (dd, J=8.2, 1.7, 1H), 6.61 (d, J=1.7, 1H), 6.04 (s, 1H), 4.90-4.68 (m, 1H), 4.32-4.01 (m, 2H), 3.95-3.68 (m, 2H), 2.04-2.10, 1H), 1.44 (s, 9H).

Step B: Preparation of 3-(2-Benzoyl-5-bromo-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester

A solution of the title compound of Step A (0.12 g, 0.28 mmol) and Dess-Martin periodane (0.17 g, 0.39 mmol) in CH₂Cl₂ (15 mL) was stirred at rt for 15 h and filtered. The resulting filtrate was concentrated and purified (SiO₂; EtOAc/Hexanes) providing the title compound (0.10 g, 84%). MS (ESI): mass calcd. for C₂₁H₂₂BrNO₄, 431.1; m/z found, 432.4 [M+H]⁺. ¹H NMR (CDCl₃): 7.70-7.64 (m, 2H), 7.55-7.45 (m, 1H), 7.40-7.31 (m, 2H), 7.27 (d, J=8.1 Hz, 1H), 7.18 (dd, J=8.0, 1.7 Hz, 1H), 6.69 (d, J=1.6 Hz, 1H), 4.72 (tt, J=6.4, 4.2 Hz, 1H), 4.16-3.97 (m, 2H), 3.59 (dd, J=10.6, 4.1 Hz, 2H), 1.46-1.25 (m, 9H).

Step C: Preparation of 2-(azetidin-3-yloxy)-4-bromo-phenyl]-phenyl-methanone

To a solution of 3-(2-benzoyl-5-bromo-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (0.10 g, 0.23 mmol) in CH₂Cl₂ (10 mL) was added 2M HCl in Et₂O (0.5 mL). After 15 h, the reaction was concentrated to give the title compound as the hydrochloride salt which was neutralized with 1N NaOH (5 mL) and extracted with CH₂Cl₂ (3×15 mL). The organic layers were combined and dried to give the title compound (0.07 g, 90%). MS (ESI): mass calcd. for C₁₆H₁₄BrNO₂, 331.0; m/z found 332.2, [M+H]⁺. ¹H NMR (CD₃OD): 7.82-7.74 (m, 2H), 7.67 (t, J=7.4 Hz, 1H), 7.54 (t, J=7.8 Hz, 2H), 7.43-7.32 (m, 2H), 5.47-5.36 (m, 1H), 4.46 (dd, J=12.4, 6.7 Hz, 2H), 3.94-3.81 (m, 2H).

Examples 275-292 were synthesized according to Example 274 using the appropriately substituted aryl magnesium halide and aldehyde.

Example 281: [2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(4-chloro-phenyl)-methanone

MS (ESI): mass calcd. for C₁₆H₁₃BrClNO₂, 365.0; m/z found, 366.0 [M+H]⁺. ¹H NMR (CD₃OD): 7.91-7.79 (m, 2H), 7.68-7.55 (m, 2H), 7.52-7.41 (m, 2H), 5.39-5.26 (m, 1H), 4.65-4.47 (m, 2H), 4.01 (d, J=7.4 Hz, 2H).

Example 282: [2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(3-chloro-phenyl)-methanone

MS (ESI): mass calcd. for C₁₆H₁₃BrClNO₂, 365.0; m/z found, 366.0 [M+H]⁺. ¹H NMR (CD₃OD): 7.77 (t, J=1.8, 1H), 7.71-7.61 (m, 2H), 7.51 (t, J=7.9, 1H), 7.44-7.34 (m, 2H), 7.17 (d, J=1.3, 1H), 5.19 (t, J=4.9, 1H), 4.45 (dd, J=12.7, 6.6, 2H), 3.89 (dd, J=12.6, 4.8, 2H).

Example 283: [4-Bromo-2-(1-methyl-azetidin-3-yloxy)-phenyl]-(3-chloro-phenyl)-methanone

Prepared according to general procedure 5 using the title compound from Example 276. MS (ESI): mass calcd. for C₁₇H₁₅BrClNO₂, 379.0; m/z found, 380.1 [M+H]⁺. ¹H NMR (CD₃OD): 7.74 (t, J=1.7, 1H), 7.71-7.60 (m, 2H), 7.51 (t, J=7.9, 1H), 7.44-7.34 (m, 2H), 7.17 (d, J=1.3, 1H), 5.19 (t, J=4.9, 1H), 4.50-4.40 (m, 2H), 3.90-3.82 (m, 2H). 2.19 (s, 3H).

Example 284: [2-(Azetidin-3-yloxy)-4-bromo-phenyl]-m-tolyl-methanone

MS (ESI): mass calcd. for C₁₇H₁₆BrNO₂, 345.0; m/z found, 346.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.67-7.48 (m, 2H), 7.43-7.13 (m, 4H), 6.90-6.74 (m, 1H), 4.98-4.86 (m, 1H), 3.80 (s, 1H), 3.52 (s, 1H), 2.40 (s, 2H), 2.02 (s, 3H).

Example 285: [2-(Azetidin-3-yloxy)-4-bromo-phenyl]-o-tolyl-methanone

MS (ESI): mass calcd. for C₁₇H₁₆BrNO₂, 345.0; m/z found, 346.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.46 (d, J=8.2, 1H), 7.36 (s, 1H), 7.27 (s, 3H), 7.23-7.10 (m, 2H), 6.75 (s, 1H), 4.81 (s, 1H), 3.69 (s, 2H), 3.32 (s, 2H), 2.44 (s, 3H).

Example 286: [2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(3-methoxy-phenyl)-methanone

MS (ESI): mass calcd. for C₁₇H₁₆BrNO₃, 361.0; m/z found, 362.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.39-7.07 (m, 6H), 6.91-6.79 (m, 1H), 4.66 (s, 1H), 3.84 (s, 3H), 3.50 (s, 2H), 2.97 (s, 2H).

Example 287: [2-(Azetidin-3-yloxy)-4-bromo-phenyl]-naphthalen-2-yl-methanone

MS (ESI): mass calcd. for C₂₀H₁₆BrNO₂, 381.0; m/z found, 382.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.19 (s, 1H), 7.96-7.85 (m, 4H), 7.65-7.50 (m, 2H), 7.39-7.21 (m, 2H), 6.85 (d, J=1.6 Hz, 1H), 4.95-4.89 m, 1H), 3.77-3.66 (m, 2H), 3.51-3.40 (m, 2H).

Example 288: [4-Bromo-2-(1-isopropyl-azetidin-3-yloxy)-phenyl]-naphthalen-2-yl-methanone

Prepared according to general procedure 3 or 4 using the title compound from Example 281. MS (ESI): mass calcd. for C₂₃H₂₂BrNO₂, 423.1; m/z found, 426.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.16-8.10 (m, 1H), 7.95-7.85 (m, 4H), 7.65-7.50 (m, 2H), 7.39-7.21 (m, 2H), 6.90-6.82 (m, 1H), 4.96-4.80 (m, 1H), 3.77-3.66 (m, 2H), 3.51-3.40 (m, 2H), 2.34-2.20 (m, 1H), 0.91 (d, J=6.1 Hz, 6H).

Example 289: [2-(Azetidin-3-yloxy)-4-bromo-phenyl]-benzo[1,3]dioxol-5-yl-methanone

MS (ESI): mass calcd. for C₁₇H₁₄BrNO₄, 375.1; m/z found, 376.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.38-7.11 (m, 4H), 6.81 (d, J=8.0 Hz, 2H), 6.06 (s, 2H), 4.94 (s, 1H), 3.81 (s, 2H), 3.59 (s, 2H).

Example 290: Benzo[1,3]dioxol-5-yl-[4-bromo-2-(1-isopropyl-azetidin-3-yloxy)-phenyl]-methanone

Prepared according to general procedure 3 or 4 using the title compound from Example 283. MS (ESI): mass calcd. for C₂₀H₂₀BrNO₄, 417.1; m/z found, 418.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.36-7.15 (m, 4H), 6.76-6.61 (m, 2H), 6.06 (d, J=4.1 Hz, 2H), 4.76-4.61 (m, 1H), 3.79-3.63 (m, 2H), 2.87-2.75 (m, 2H), 2.34-2.18 (m, 1H), 0.90 (d, J=6.2 Hz, 6H).

Example 291: [2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(4-methoxy-phenyl)-methanone

MS (ESI): mass calcd. for C₁₇H₁₆BrNO₃, 361.0; m/z found, 362.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.38-7.12 (m, 6H), 6.96-6.83 (m, 1H), 4.65 (s, 1H), 3.84 (s, 3H), 3.54 (s, 2H), 2.99 (s, 2H).

Example 292: [2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(4-chloro-3-fluoro-phenyl)-methanone

MS (ESI): mass calcd. for C₁₆H₁₂BrClFNO₂, 383.0; m/z found, 384.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.63-7.40 (m, 3H), 7.38-7.15 (m, 2H), 6.88-6.67 (m, 1H), 4.91 (s, 1H), 3.80 (s, 2H), 3.50 (s, 2H).

Example 293: [2-(Azetidin-3-yloxy)-4-bromo-phenyl]-(3,4-dichloro-phenyl)-methanone

MS (ESI): mass calcd. for C₁₆H₁₂BrCl₂NO₂, 399.0; m/z found, 400.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.83 (d, J=1.9 Hz, 1H), 7.63-7.51 (m, 2H), 7.35-7.19 (m, 2H), 6.82 (d, J=1.6 Hz, 1H), 5.00-4.85 (m, 1H), 4.02-3.31 (m, 4H).

Example 294: [2-(Azetidin-3-yloxy)-4-chloro-phenyl]-naphthalen-2-yl-methanone

MS (ESI): mass calcd. for C₂₀H₁₆ClNO₂, 337.1; m/z found, 338.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.19 (s, 1H), 7.98-7.85 (m, 3H), 7.63-7.37 (m, 4H), 7.10 (dd, J=8.1, 1.7 Hz, 1H), 6.70 (d, J=1.6 Hz, 1H), 4.97-4.84 (m, 1H), 3.74 (s, 2H), 3.50-3.37 (m, 2H).

Example 295: [2-(Azetidin-3-yloxy)-4-chloro-phenyl]-benzo[1,3]dioxol-5-yl-methanone

MS (ESI): mass calcd. for C₁₇H₁₄ClNO₄, 331.1; m/z found, 332.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.35-7.21 (m, 3H), 7.04 (dd, J=8.1, 1.8 Hz, 1H), 6.82 (d, J=8.1 Hz, 1H), 6.65 (d, J=1.7 Hz, 1H), 6.05 (d, J=8.9 Hz, 2H), 5.02-4.87 (m, 1H), 3.86 (s, 2H), 3.62 (s, 2H).

Example 296: Benzo[1,3]dioxol-5-yl-[4-chloro-2-(1-isopropyl-azetidin-3-yloxy)-phenyl]-methanone

Prepared according to general procedure 3 or 4 using the title compound from Example 289. MS (ESI): mass calcd. for C₂₀H₂₀ClNO₄, 373.1; m/z found, 374.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.40-7.25 (m, 4H), 6.76-6.61 (m, 2H), 6.10-6.04 (m, 2H), 4.81-4.64 (m, 1H), 3.75-3.63 (m, 2H), 2.85-2.74 (m, 2H), 2.28-2.18 (m, 1H), 0.96 (d, J=6.1 Hz, 6H).

Example 297: [2-(Azetidin-3-yloxy)-4-chloro-phenyl]-(4-chloro-phenyl)-methanone

MS (ESI): mass calcd. for C₁₆H₁₃Cl₂NO₂, 321.0; m/z found, 322.2 [M+H]⁺. ¹H NMR (CD₃OD): 7.79-7.62 (m, 2H), 7.56-7.35 (m, 3H), 7.16 (s, 1H), 7.00-6.76 (m, 1H), 5.19-5.08 (m, 1H), 4.16 (s, 2H), 3.87 (s, 1H), 3.49 (s, 1H).

Example 298: [2-(Azetidin-3-yloxy)-4-chloro-phenyl]-(3-chloro-phenyl)-methanone

MS (ESI): mass calcd. for C₁₆H₁₃Cl₂NO₂, 321.0; m/z found, 322.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.70 (t, J=1.7, 1H), 7.62 (dd, J=7.8, 1.3 Hz, 1H), 7.58-7.51 (m, 1H), 7.47-7.34 (m, 2H), 7.12 (dd, J=8.2, 1.8 Hz, 1H), 6.61 (d, J=1.7 Hz, 1H), 4.87-4.68 (m, 1H), 4.21-4.13 (m, 2H), 3.67 (dd, J=9.9, 4.0 Hz, 2H).

Biological Assays

r5-HT₇ Binding Assay

Receptor binding was performed using membrane fractions prepared from the HEK-293 cell line recombinantly expressing rat 5-HT₇ receptors (NCBI accession NM_022938). Compound affinity for the rat 5-HT₇ receptor subtype was evaluated by competitive radioligand binding assays using 5-carboxamido[³H]tryptamine ([³H]5-CT) (Amersham Biosciences, cat. 90000403) detection. HitHunter™ cAMP assays are in-vitro based competitive immunoassays. The assay was performed on the HEK-293 cell line stably transfected with r5-HT₇ receptor. Cells were pre-incubated with test compounds for 10 minutes. For antagonist testing, the cells were then challenged with 100 nM 5-CT for 20 minutes. Cells were then lysed and cAMP measured according to manufacturers protocol (Amersham, cat. NET791250UC) or [³H]mesulergine (Amersham, cat. TRK1041). The assay was performed on membranes prepared from HEK-293 cells stably transfected with h5-HT₆. Following centrifugation, membranes were resuspended and incubated for 60 min at room temperature with 1.7 nM [³H]LSD in the presence of increasing concentration of test compounds. Nonspecific binding was defined in the presence of 10 μM clozapine (Tocris, cat. TRK1068). Homogenized HEK-293 membranes expressing the human SERT were incubated in 50 mM Tris-HCl (pH 7.5), 120 mM NaCl, 5 mM KCl with [³H]-citalopram (3 nM) with or without test compounds. Nonspecific binding was determined in the presence of 10 μM fluoxetine. Radioactivity readouts and K_(i) values were performed as previously described for r5-HT₇. Table 1 shows assay results for exemplified compounds of the invention. Compounds were assayed in their free form or as salts, as indicated in the Examples section above.

TABLE 1 5HT7- hSERT h5HT6 h5HT2_(A) h5HT2_(B) h5HT2_(C) R5HT7 RAT binding binding binding binding binding cAMP EX. Ki (uM) Ki (uM) K_(i) (uM) K_(i) (uM) K_(i) (uM) K_(i) (uM) pK_(b) 1 0.009 0.048 ND ND ND ND 7.9 2 0.012 0.001 0.047 0.042 0.074 0.760 7.5 3 0.018 0.381 ND ND ND ND 8.6 4 0.008 ND ND ND ND ND 9.2 5 0.008 0.194 ND ND ND ND 8.3 6 0.006 0.249 ND ND ND ND 8.4 7 0.010 0.023 ND ND ND ND 7.2 8 0.006 0.004 ND ND ND ND 8.1 9 0.011 0.002 ND ND ND ND 7.7 10 0.007 0.039 0.050 ND ND ND 8.2 11 0.053 ND ND ND ND ND ND 12 0.011 0.006 ND ND ND ND 8.5 13 0.004 0.006 ND ND ND ND 8.4 14 0.012 0.052 ND ND ND ND 6.8 15 0.017 0.005 0.045 ND ND ND 6.2 16 0.100 ND ND ND ND ND ND 17 0.010 0.004 0.039 ND ND ND 7.3 18 0.005 0.435 ND ND ND ND 8.8 19 0.004 0.396 ND ND ND ND 8.7 20 0.008 ND ND ND ND ND ND 21 0.020 ND ND ND ND ND ND 22 0.125 0.028 ND ND ND ND ND 23 0.121 ND ND ND ND ND ND 24 0.190 ND ND ND ND ND ND 25 0.018 0.019 ND ND ND ND 7.4 26 0.025 0.013 ND ND ND ND ND 27 0.229 1.679 ND ND ND ND ND 28 0.049 0.683 ND ND ND ND ND 29 0.083 0.027 ND 0.225 0.529 1.109 6.9 30 0.105 ND ND ND ND ND ND 31 0.100 0.090 ND ND ND ND ND 32 0.053 0.029 ND ND ND ND ND 33 0.007 0.008 ND ND ND ND 7.8 34 0.029 0.001 ND ND ND ND 7.4 35 0.023 0.003 ND ND ND ND 6.0 36 0.015 0.036 ND ND ND ND 6.1 37 0.008 0.007 0.089 ND ND ND 6.9 38 0.006 0.100 0.036 ND ND ND 8.0 39 0.007 0.004 ND ND ND ND 8.5 40 0.009 0.043 ND ND ND ND 7.4 41 0.130 ND ND ND ND ND ND 42 0.035 0.578 ND ND ND ND ND 43 0.015 0.086 ND ND ND ND ND 44 0.087 ND ND ND ND ND ND 45 3.159 0.197 ND ND ND ND ND 46 0.102 ND ND ND ND ND ND 47 0.011 0.021 ND ND ND ND ND 48 0.088 ND ND ND ND ND ND 49 0.013 0.040 ND ND ND ND 7.6 50 0.010 0.005 ND ND ND ND 7.5 51 0.387 0.086 ND ND ND ND ND 52 0.110 0.089 ND ND ND ND ND 53 0.260 0.464 ND ND ND ND ND 54 0.006 0.028 0.077 ND ND ND 8.1 55 0.171 ND ND ND ND ND ND 56 8.999 ND ND ND ND ND ND 57 0.042 ND ND ND ND ND ND 58 0.120 ND ND ND ND ND ND 59 0.027 0.353 0.084 ND ND ND 7.8 60 0.250 ND ND ND ND ND ND 61 0.036 ND ND ND ND ND ND 62 0.034 ND ND ND ND ND ND 63 0.007 0.048 ND ND ND ND 7.6 64 0.017 0.043 ND ND ND ND ND 65 0.011 0.014 0.041 ND ND ND 6.9 66 0.010 ND ND ND ND ND 7.3 67 0.013 ND ND ND ND ND 6.4 68 0.017 ND ND ND ND ND 6.2 69 0.094 ND ND ND ND ND ND 70 0.174 ND ND ND ND ND ND 71 0.143 ND ND ND ND ND ND 72 0.270 ND ND ND ND ND ND 73 0.023 2.177 0.012 ND ND ND 6.6 74 0.011 ND ND ND ND ND ND 75 8.999 ND ND ND ND ND ND 76 5.000 ND ND ND ND ND ND 77 0.153 5.000 ND ND ND ND ND 78 0.710 ND ND ND ND ND ND 79 0.026 0.003 ND 0.069 0.248 0.290 7.3 80 >10 ND ND ND ND ND ND 81 0.097 1.170 ND 0.076 0.367 0.590 ND 82 0.198 ND ND ND ND ND ND 83 0.016 0.024 ND ND ND ND ND 84 0.034 0.061 ND ND ND ND ND 85 0.095 0.404 ND ND ND ND ND 86 0.038 0.121 ND ND ND ND ND 87 0.240 ND ND ND ND ND ND 88 0.681 ND ND ND ND ND ND 89 0.025 0.242 ND ND ND ND ND 90 0.920 ND ND 0.020 0.083 0.160 ND 91 0.500 ND ND 0.005 0.050 0.120 ND 92 0.260 ND ND 0.014 0.028 0.110 ND 93 0.140 ND ND 0.003 0.013 0.051 ND 94 >2.499 ND ND 0.032 0.250 0.069 ND 95 0.009 ND ND ND ND ND ND 96 0.013 ND ND ND ND ND ND 97 0.034 ND ND ND ND ND ND 98 0.023 ND ND ND ND ND ND 99 0.005 ND ND ND ND ND ND 100 0.150 ND ND ND ND ND ND 101 0.005 0.152 0.746 0.317 0.203 0.933 ND 102 0.376 0.954 ND ND ND ND ND 103 0.027 ND ND ND ND ND ND 104 0.166 ND ND ND ND ND ND 105 0.023 0.193 ND ND ND ND 7.3 106 0.075 ND ND ND ND ND ND 107 0.090 ND ND ND ND ND ND 108 0.036 5    ND ND ND ND ND 109 0.005 2.900 ND ND ND ND ND 110 0.090 0.554 ND ND ND ND ND 111 0.010 0.118 0.268 0.073 0.069 0.331 ND 112 0.023 0.138 ND ND ND ND 7.5 113 0.011 0.058 0.496 0.206 0.122 0.490 ND 114 0.014 0.075 ND ND ND ND 7.5 115 0.033 0.202 ND ND ND ND ND 116 0.068 ND ND ND ND ND ND 117 0.041 0.071 ND ND ND ND ND 118 0.090 ND ND ND ND ND ND 119 0.288 ND ND ND ND ND ND 120 0.040 ND ND ND ND ND ND 121 0.033 0.164 ND ND ND ND ND 122 0.210 ND ND ND ND ND ND 123 0.042 0.025 ND ND ND ND ND 124 0.043 0.020 ND ND ND ND ND 125 0.104 ND ND ND ND ND ND 126 0.038 ND ND ND ND ND ND 127 0.063 ND ND ND ND ND ND 128 0.127 ND ND ND ND ND ND 129 0.903 ND ND ND ND ND ND 130 0.371 ND ND ND ND ND ND 131 0.073 1.355 ND ND ND ND ND 132 0.456 ND ND ND ND ND ND 133 0.591 ND ND ND ND ND ND 134 3.827 ND ND ND ND ND ND 135 0.015 0.096 1.275 0.140 0.027 0.755 ND 136 0.029 0.098 ND ND ND ND ND 137 0.472 ND ND ND ND ND ND 138 0.042 ND ND ND ND ND ND 139 0.189 ND ND ND ND ND ND 140 0.230 ND ND ND ND ND ND 141 0.450 ND ND ND ND ND ND 142 0.091 0.613 ND ND ND ND ND 143 0.215 ND ND ND ND ND ND 144 0.304 ND ND ND ND ND ND 145 0.040 0.773 ND ND ND ND ND 146 0.012 0.059 0.558 ND ND ND 8.1 147 0.211 ND ND ND ND ND ND 148 2.000 ND ND ND ND ND ND 149 >10 ND ND ND ND ND ND 150 0.010 0.013 ND ND ND ND 8.0 151 0.040 ND ND ND ND ND 7.5 152 0.019 0.025 ND ND ND ND 7.4 153 0.084 ND ND ND ND ND 7.2 154 0.018 0.013 ND ND ND ND 7.7 155 0.019 0.045 ND ND ND ND ND 156 0.252 ND ND ND ND ND <5   157 0.010 0.181 ND ND ND ND 8.3 158 0.015 0.067 ND 0.008 0.036 0.146 8.0 159 0.017 0.021 ND 0.006 0.041 0.196 8.1 160 0.015 0.210 ND 0.005 0.025 0.146 8.3 161 0.028 0.060 ND ND ND ND 7.8 162 5.000 ND ND ND ND ND ND 163 0.766 ND ND ND ND ND ND 164 0.033 0.008 ND 0.024 0.030 0.181 ND 165 0.016 0.095 ND ND ND ND ND 166 1.269 ND ND ND ND ND ND 167 0.167 ND ND ND ND ND ND 168 0.130 ND ND 0.008 0.021 0.048 ND 169 0.119 ND ND ND ND ND ND 170 5.000 ND ND ND ND ND ND 171 0.007 0.234 ND ND ND ND ND 172 5.000 ND ND ND ND ND ND 173 0.007 0.056 ND ND ND ND 8.1 174 0.006 0.042 ND ND ND ND 8.2 175 0.011 0.004 ND ND ND ND ND 176 0.024 0.075 ND ND ND ND ND 177 0.012 0.262 0.123 0.035 0.056 0.140 ND 178 0.017 0.131 ND ND ND ND ND 179 0.360 ND ND ND ND ND ND 180 0.813 ND ND ND ND ND ND 181 0.019 0.967 ND ND ND ND 7.7 182 0.076 0.514 ND ND ND ND ND 183 0.110 ND ND ND ND ND ND 184 0.023 0.124 ND 0.005 0.012 0.038 7.3 185 0.006 0.029 0.177 0.008 0.007 0.091 ND 186 0.005 0.053 0.033 0.014 0.008 0.079 ND 187 0.036 0.340 ND ND ND ND ND 188 0.034 0.065 ND 0.008 0.028 0.143 ND 189 0.138 ND ND ND ND ND ND 190 0.008 0.211 ND 0.014 0.069 0.056 ND 191 0.008 0.007 ND 0.008 0.011 0.053 ND 192 0.008 0.088 ND 0.009 0.022 0.140 ND 193 0.005 0.009 ND 0.011 0.014 0.071 ND 194 0.004 0.141 ND 0.004 0.195 0.081 ND 195 0.002 0.060 0.027 0.010 0.004 0.042 ND 196 0.359 0.053 ND ND ND ND ND 197 1.421 ND ND ND ND ND ND 198 1.462 ND ND ND ND ND ND 199 0.018 0.128 ND 0.103 1.223 0.526 7.4 200 0.031 0.224 ND 0.605 7.568 5.000 6.8 201 0.031 0.056 ND 0.067 0.184 0.498 7.3 202 0.066 ND ND ND ND ND ND 203 0.024 0.271 ND ND ND ND 7.7 204 0.027 ND ND ND ND ND ND 205 0.027 ND ND ND ND ND ND 206 0.021 ND ND ND ND ND ND 207 0.020 ND ND ND ND ND 7.8 208 0.365 0.303 ND ND ND ND ND 209 0.013 0.020 ND ND ND ND 7.7 210 0.506 ND ND ND ND ND ND 211 8.999 ND ND ND ND ND ND 212 0.053 0.041 ND ND ND ND ND 213 4.589 ND ND ND ND ND ND 214 8.999 1.693 ND ND ND ND ND 215 0.011 0.044 ND 0.006 0.017 0.026 ND 216 0.016 0.036 ND ND ND ND ND 217 0.034 0.113 ND ND ND ND ND 218 0.069 ND ND ND ND ND ND 219 0.009 0.068 ND ND ND 0.031 ND 220 0.493 0.789 ND ND ND ND ND 221 0.147 5    ND ND ND ND ND 222 0.018 2.114 ND ND ND 1.009 ND 223 0.145 8.999 ND ND ND ND ND 224 0.068 ND ND ND ND ND ND 225 2.669 ND ND ND ND ND ND 226 0.840 ND ND ND ND ND ND 227 0.336 ND ND ND ND ND ND 228 0.009 0.072 ND ND ND ND ND 229 0.003 0.925 ND ND ND ND ND 230 0.006 1.203 ND ND ND ND ND 231 0.015 4.481 ND ND ND ND ND 232 0.003 0.001 ND ND ND ND ND 233 0.027 0.023 ND ND ND ND ND 234 0.130 ND ND ND ND ND ND 235 0.665 ND ND ND ND ND ND 236 0.831 ND ND ND ND ND ND 237 0.120 ND ND ND ND ND ND 238 0.200 ND ND ND ND ND ND 239 0.233 ND ND ND ND ND ND 240 0.252 ND ND ND ND ND ND 241 0.263 ND ND ND ND ND ND 242 0.273 ND ND ND ND ND ND 243 0.461 ND ND ND ND ND ND 244 0.020 5.000 0.046 ND ND ND 6.6 245 0.009 ND ND ND ND ND 6.7 248 0.043 ND ND ND ND ND ND 249 0.020 ND ND ND ND ND ND 250 0.017 ND ND ND ND ND ND 251 0.011 ND ND ND ND ND 6.8 252 0.007 0.060 ND ND ND ND 7.2 253 0.018 ND ND ND ND ND 6.3 254 0.019 ND ND ND ND ND ND 255 0.196 ND ND ND ND ND ND 256 0.160 ND ND ND ND ND ND 257 0.021 ND ND ND ND ND 6.3 258 0.023 ND ND ND ND ND 6.3 259 0.460 ND ND ND ND ND ND 260 0.016 0.002 ND ND ND ND 6.0 261 1.604 ND ND ND ND ND ND 262 0.031 0.112 ND ND ND ND ND 263 0.544 ND ND ND ND ND ND 264 1.097 ND ND ND ND ND ND 265 0.130 ND ND ND ND ND ND 266 >10 ND ND 0.150 0.130 0.230 ND 267 2.300 ND ND 0.120 0.065 0.210 ND 268 0.820 ND ND 0.150 0.130 0.380 ND 269 >10 ND ND 0.190 0.500 0.400 ND 270 1.000 ND ND 0.120 0.075 0.240 ND 271 0.660 ND ND 0.078 0.098 0.350 ND 272 >10 ND ND 0.220 0.310 0.330 ND 273 >5 ND ND 0.082 0.160 0.150 ND 274 8.600 ND ND 0.100 0.170 0.230 ND 275 >10 ND ND 0.530 0.910 0.220 ND 276 >10 ND ND 0.084 0.190 0.120 ND 277 5.500 ND ND 0.410 0.270 0.120 ND 278 >10 ND ND 1.400 1.300 0.330 ND 279 0.025 ND ND ND ND ND ND 280 0.098 ND ND ND ND ND ND 281 0.048 ND ND ND ND ND 6.5 282 0.039 ND ND ND ND ND 6.7 283 0.050 ND ND ND ND ND ND 284 0.019 ND ND ND ND ND ND 285 3.000 ND ND ND ND ND ND 286 0.039 ND ND ND ND ND ND 287 0.015 0.014 ND ND ND ND 7.2 288 0.059 ND ND ND ND ND ND 289 0.034 0.437 ND ND ND ND 7.4 290 0.143 ND ND ND ND ND ND 291 0.034 ND ND ND ND ND ND 292 0.074 ND ND ND ND ND ND 293 0.051 ND ND ND ND ND ND 294 0.072 ND ND ND ND ND ND 295 0.226 ND ND ND ND ND ND 296 0.181 ND ND ND ND ND ND 297 0.150 ND ND ND ND ND ND 298 0.102 ND ND ND ND ND ND *ND symbolizes not determined.

While the invention has been illustrated by reference to exemplary and preferred embodiments, it will be understood that the invention is intended not to be limited by the foregoing detailed description, but to be defined by the appended claims as properly construed under principles of patent law. 

What is claimed is:
 1. A compound selected from the group consisting of (a) compounds of Formula (I):

wherein R¹ is —H, or —C₁₋₄alkyl; m is 1; n is 2; R² and R³ are each independently —H or —C₁₋₄alkyl; R⁴ is —H; L is —O—; Z is —O—, or —OCH(R^(b))—; where R^(b) is —H; R⁵ is: a phenyl group, unsubstituted or substituted with one, two, or three R^(g) substituents; where each R^(g) substituent is selected from the group consisting of: —C₁₋₆alkyl, —OH, —OC₁₋₆alkyl, —CN, —NO₂, —C(O)C₁₋₆alkyl, —S(O)₀₋₂—C₁₋₆alkyl, —OS(O)₀₋₂—C₁₋₆alkyl, —SO₂CF₃, —SCF₃, halo, —CF₃, —OCF₃, —CO₂H, —CO₂C₁₋₆alkyl, —CH₂OH, monocyclic cycloalkyl, phenyl, thiophenyl, benzhydryl, and oxadiazolyl; or two R^(g) substituents taken together form —OCH₂O—, —OCF₂O—, or —OCH₂CH₂O—; X is C; and R⁶ and R⁷ are each independently —H, and halo; and (b) pharmaceutically acceptable salts of the compounds of Formula (I).
 2. A compound as defined in claim 1, wherein R¹ is —H, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, or —C(CH₃)₃.
 3. A compound as defined in claim 2, wherein R¹ is —H.
 4. A compound as defined in claim 1, wherein R² is —H or —CH₃.
 5. A compound as defined in claim 1, wherein R³ is —H or —CH₃.
 6. A compound as defined in claim 1, wherein R² and R³ are each —H.
 7. A compound as defined in claim 1, wherein Z is —O—.
 8. A compound as defined in claim 1, wherein Z is —OCH₂.
 9. A compound as defined in claim 1, wherein R⁵ is phenyl, optionally substituted with halo, —OCH₃, —OSO₂CH₃, and CF₃.
 10. A compound as defined in claim 1, wherein R⁵ is selected from the group consisting of: phenyl, 3- or 4-bromo-phenyl, 2-, 3- or 4-chloro-phenyl, 3,4-dichloro-phenyl, 3- or 4-cyano-phenyl, 2-, 3- or 4-fluoro-phenyl, 3-chloro-4-fluoro-phenyl, 4-chloro-3-fluoro-phenyl, 4-chloro-3-trifluoromethyl-phenyl, 3-chloro-4-trifluoromethoxy-phenyl, 2,4-difluoro-phenyl, 2-fluoro-4-trifluoromethyl-phenyl, 3-fluoro-4-trifluoromethyl-phenyl, 4-fluoro-3-trifluoromethyl-phenyl, 3- or 4-methyl-phenyl, 3- or 4-methylsulfanyl-phenyl, 3- or 4-methoxy-phenyl, 3-chloro-4-methoxy-phenyl, 3-methanesulfonyloxy-phenyl, 3- or 4-methoxy-phenyl, 3-trifluoromethoxy-phenyl, 2-, 3- or 4-trifluoromethyl-phenyl, 4-fluoro-3-trifluoromethyl-phenyl, 3- or 4-trifluoromethyl sulfanyl-phenyl, and 3-trifluoromethoxy-phenyl.
 11. A compound as defined in claim 1, wherein R⁶ and R⁷ are H.
 12. A compound as defined in claim 1, wherein R⁶ is —H or Cl.
 13. A compound as defined in claim 1, wherein R⁶ is —H or Cl and R⁷ is —H, Br, or Cl.
 14. A compound as defined in claim 1, selected from the group consisting of: (R)-3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine; (R)-3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine; (R)-3-[5-Chloro-2-(2-chloro-benzyloxy)-phenoxy]-pyrrolidine; (R)-3-[5-Chloro-2-(2-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine; (R)-3-(2-Benzyloxy-4-chloro-phenoxy)-pyrrolidine; (R)-3-(2-Benzyloxy-4-chloro-phenoxy)-1-methyl-pyrrolidine; (R)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine; (R)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine; (S)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine; (±)-3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine; (±)-3-[5-Bromo-2-(3-methoxy-benzyloxy)-phenoxy]-1-methyl-pyrrolidine; (±)-3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine; (±)-3-(2-Benzyloxy-5-bromo-phenoxy)-1-methyl-pyrrolidine; (±)-Methanesulfonic acid 3-[4-bromo-2-(1-methyl-pyrrolidin-3-yloxy)-phenoxymethyl]-phenyl ester; (±)-Methanesulfonic acid 3-[2-(1-methyl-pyrrolidin-3-yloxy)-phenoxymethyl]-phenyl ester; (S)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-pyrrolidine; (R)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-pyrrolidine; (R)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-1-methyl-pyrrolidine; (S)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-pyrrolidine; (R)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-pyrrolidine; (R)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-1-methyl-pyrrolidine; (S)-3-(4-Chloro-2-o-tolyloxy-phenoxy)-pyrrolidine; (S)-3-(4-Chloro-2-m-tolyloxy-phenoxy)-pyrrolidine; (S)-3-[4-Chloro-2-(4-fluoro-3-methyl-phenoxy)-phenoxy]-pyrrolidine; (S)-3-[4-Chloro-2-(4-chloro-phenoxy)-phenoxy]-pyrrolidine; (S)-3-[4-Chloro-2-(3-chloro-phenoxy)-phenoxy]-pyrrolidine; (S)-3-[2-(4-Bromo-phenoxy)-4-chloro-phenoxy]-pyrrolidine; (S)-3-[4-Chloro-2-(4-isopropyl-phenoxy)-phenoxy]-pyrrolidine; and (±)-3-[5-Bromo-2-(4-bromo-phenoxy)-phenoxy]-1-ethyl-pyrrolidine; and pharmaceutically acceptable salts thereof.
 15. A pharmaceutical composition, comprising an effective amount of at least one compound selected from compounds of Formula (I):

wherein R¹ is —H, or —C₁₋₄alkyl; m is 1; n is 2; R² and R³ are each independently —H or —C₁₋₄alkyl; R⁴ is —H; L is —O—; Z is —O—, or —OCH(R^(b))— where R^(b) is —H; R⁵ is: a phenyl group, unsubstituted or substituted with one, two, or three R^(g) substituents; where each R^(g) substituent is selected from the group consisting of: —C₁₋₆alkyl, —OH, —OC₁₋₆alkyl, —CN, —NO₂, —C(O)C₁₋₆alkyl, —S(O)₀₋₂—C₁₋₆alkyl, —OS(O)₀₋₂—C₁₋₆alkyl, —SO₂CF₃, —SCF₃, halo, —CF₃, —OCF₃, —CO₂H, —CO₂C₁₋₆alkyl, —CH₂OH, monocyclic cycloalkyl, phenyl, thiophenyl, benzhydryl, and oxadiazolyl; or two R^(g) substituents taken together form —OCH₂O—, —OCF₂O—, or —OCH₂CH₂O—; X is C; and R⁶ and R⁷ are each independently —H, and halo; and (b) pharmaceutically acceptable salts of the compounds of Formula (I).
 16. A pharmaceutical composition according to claim 15, wherein said at least one compound is selected from the group consisting of: (R)-3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine; (R)-3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine; (R)-3-[5-Chloro-2-(2-chloro-benzyloxy)-phenoxy]-pyrrolidine; (R)-3-[5-Chloro-2-(2-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine; (R)-3-(2-Benzyloxy-4-chloro-phenoxy)-pyrrolidine; (R)-3-(2-Benzyloxy-4-chloro-phenoxy)-1-methyl-pyrrolidine; (R)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine; (R)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine; (S)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine; (±)-3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine; (±)-3-[5-Bromo-2-(3-methoxy-benzyloxy)-phenoxy]-1-methyl-pyrrolidine; (±)-3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine; (±)-3-(2-Benzyloxy-5-bromo-phenoxy)-1-methyl-pyrrolidine; (±)-Methanesulfonic acid 3-[4-bromo-2-(1-methyl-pyrrolidin-3-yloxy)-phenoxymethyl]-phenyl ester; (±)-Methanesulfonic acid 3-[2-(1-methyl-pyrrolidin-3-yloxy)-phenoxymethyl]-phenyl ester; (S)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-pyrrolidine; (R)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-pyrrolidine; (R)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-1-methyl-pyrrolidine; (S)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-pyrrolidine; (R)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-pyrrolidine; (R)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-1-methyl-pyrrolidine; (S)-3-(4-Chloro-2-o-tolyloxy-phenoxy)-pyrrolidine; (S)-3-(4-Chloro-2-m-tolyloxy-phenoxy)-pyrrolidine; (S)-3-[4-Chloro-2-(4-fluoro-3-methyl-phenoxy)-phenoxy]-pyrrolidine; (S)-3-[4-Chloro-2-(4-chloro-phenoxy)-phenoxy]-pyrrolidine; (S)-3-[4-Chloro-2-(3-chloro-phenoxy)-phenoxy]-pyrrolidine; (S)-3-[2-(4-Bromo-phenoxy)-4-chloro-phenoxy]-pyrrolidine; (S)-3-[4-Chloro-2-(4-isopropyl-phenoxy)-phenoxy]-pyrrolidine; and (±)-3-[5-Bromo-2-(4-bromo-phenoxy)-phenoxy]-1-ethyl-pyrrolidine; and pharmaceutically acceptable salts thereof. 